CN102159202A

CN102159202A - Methods of administering topical antifungal formulations for treatment of fungal infections

Info

Publication number: CN102159202A
Application number: CN2009801337541A
Authority: CN
Inventors: G·策维克; U·菲尔
Original assignee: TDT Ltd
Current assignee: TDT Ltd
Priority date: 2008-07-23
Filing date: 2009-07-23
Publication date: 2011-08-17
Also published as: US20100086504A1; WO2010010470A2; MX2011000932A; JP2011529038A; NI201100025A; US7820720B2; AU2009275230A1; CL2011000135A1; US20100104633A1; EP2317993A2; WO2010010470A3; PE20110642A1; CO6351719A2; IL210813A0; KR20110039357A; CA2731455A1; ECSP11010818A

Abstract

The present invention relates to topical antifungal formulations comprising one or more antifungal (e.g., terbinafme), a lipid and a surfactant, and to uses thereof for the treatment of skin and nail fungal infections.

Description

Use the method for local antifungal preparation treatment fungal infection

Priority

The application requires the U.S. Provisional Application submitted on July 23rd, 2008 number 61/083,115, the U.S. Provisional Application of submitting on October 2nd, 2008 number 61/102,111, the U.S. Provisional Application of submitting on February 5th, 2009 number 61/150, the interests of the U.S. Provisional Application of submitting on April 9th, 187 and 2009 number 61/162,122.These the application in each piece content hereby by reference integral body incorporate this paper into.

1. technical field

The present invention relates to comprise the local antifungal preparation of one or more antifungal, lipid (lipid) and surfactant, and be used for the treatment of the purposes of skin and fingernail (nail) fungal infection.

2. background technology

Tinea unguium is the fungal infection of fingernail (fingernail) and toenail (toenail), and it causes fingernail thickening, variable color, division and fingernail to rise from nail matrix.This disease is caused by dermophyte, and in general crowd, particularly in older individuals, have a high incidence.Tinea unguium is caused by trichophyton (T.rubrum), Trichophyton mentagrophytes (T.mentagrophytes) and Epidermophyton floccosum (E.floccusum) the most commonly.Tinea unguium owing to non-dermatophytosis is caused by Candida (such as Candida albicans (Candida albicans)) usually, and more may (with comparing) cause invasive fingernail disease in toenail in the fingernail of immunocompetence individuality.

The ratio of tinea unguium is different with the crowd who considers.The research to general American population recently discloses 2% to 3% prevalence, and has reported 13% ratio (people such as Elewski, J.Am.Acad.Dermatol.2000 in the research of Finland's report; 42 (1) (Pt 1): people such as 1-20. and Heikkila, Br.J.Dermatol.1995; 133 (5): 699-703).Tinea unguium may influence 40 to 60 years old the people (people's U.S. Patent Publication No. 2006/0067898 such as Kepka) up to about 15%.

Terbinafine is the antifungal agent (Lan Meishu that indicates at present as the oral therapy of tinea unguium treatment ^TM, Novartis International AG, Basel, Switzerland).Other treatment selects may cause (comprising the infected fingernail of chemistry or exenterate) dorsal part of nail matrix shrinkage and nail matrix to disconnect.

In this part of the application,, be not to recognize that this list of references constitutes the application's prior art to the quoting of any list of references.

3. summary of the invention

The invention provides the topical formulations of one or more antifungal, it can be used for the treatment of human experimenter's fungal infection.Local antifungal preparation of the present invention is included in one or more antifungal and one or more lipids and one or more surfactants in the pharmaceutically acceptable carrier.In certain embodiments, described antifungal is the salt of terbinafine, terbinafine or the derivant or the analog of terbinafine, and it is independent or combined with one or more antifungal.In certain embodiments, described antifungal is an abafungin; acrisorcin; the A Bakang azoles; albendazole; amorolfine; amphotericin B; anidulafungin; my health azoles; azithromycin; becliconazole; benzo dithiazole (benzodithiazole); bifonazole; butoconazole; butenafine; calbistrin; Caspofungin; N-chlorine taurine; 5,7-dichloro-8-hydroxyquinoline; chlorphenesin; ciclopirox; Cioteronel; clotrimazole; croconazole; cytoporins; deoxymulundocandin; eberconazole; econazole; Yi Fengu monoclonal antibody (efungumab); fenticonazole; the flavonoid sugar glycoside; fluconazol; flucytosine; flutrimazole; fosfluconazole; genaconazole; gentian violet; griseofulvin; griseofulvin PEG; haloprogin; R 63373; isoconazole; itraconazole; ketoconazole; lanoconazole; letrazuril; liranaftate; the Lu Likang azoles; Mi Kafen is clean; miconazole; Mycophenolic Acid; naftifine; natamycin; nitazoxanide; antifungal based on nitroethylene; nystatin; omoconazole; oxiconazole; polyene macrolide; polyene macrolide; posaconazole; general Miconazole; quinolone analogs; rapamycin; ravuconazole; rilopirox; samidazole; Sertaconazole; sitamaquine; sordaricin; squalestatin; Squalene; squalene epoxidase inhibitor; sulconazole; sultriecin; tafenoquine; terconazole (triaconazole); tioconazole; tolnaftate; voriconazole or formula I chemical compound:

Or single enantiomer, the mixture of enantiomer or the mixture of its diastereomer; Or its pharmaceutically acceptable solvate, hydrate or salt; Wherein R is C _1-12Alkyl, C _1-12Acyl group or heteroaryl-C _6-14Aryl; X is a halogen; Y is N or CH; And Z is CH ₂Or O.In certain embodiments, local antifungal preparation of the present invention comprises terbinafine, one or more phospholipid and one or more nonionic surfactant.In certain embodiments, local antifungal preparation of the present invention comprises terbinafine and extra antifungal, one or more phospholipid and one or more nonionic surfactant.In certain embodiments, local antifungal preparation provided herein comprises: itraconazole, ketoconazole, posaconazole, Saperconazole, SCH-50002, terconazole (triaconazole), butenafine and griseofulvin and one of its hydrate, solvate and salt; One or more phospholipid and one or more nonionic surfactant.In certain embodiments, antifungal preparation provided herein comprises the antifungal from following antifungal classification: including, but not limited to, antimetabolite, Macrolide, echinocandin (echinocadins), imidazoles, triazole type, benzylamine class, griseofulvin, allylamine, polyalkenes, thiocarbamates and halogenated phenol ethers.This paper disclosure relates to topical formulations, such as solution, suspensoid (suspension), gel, fluid gel, Emulsion, Emulsion gel, lotion, ointment, film forming solution (film forming solution), ointment, spray and lacquer agent (lacquer).

Particularly, antifungal preparation of the present invention can be used for the treatment of or prevent human experimenter's tinea unguium.Antifungal preparation of the present invention also can be used for the treatment of or prevent the fungal infection of skin, includes, but are not limited to tinea corporis, tinea cruris, tinea pedis, pityriasis versicolor (tinea).Antifungal preparation of the present invention also by Trichophyton (for example can be used for the treatment of usually, T.rubru, Trichophyton mentagrophytes (T.mentagrophytes), Trichophyton verrucosum (T.verrucosum), Trichophyton violaceum (T.violaceum)), the fungal infection that causes of Microsporum canis (Microsporum canis), Epidermophyton floccosum (E.floccusum) and candida yeasts (for example, Candida albicans (Candida albicans)) and Malassezia furfur (Malasseziafurfur).

Antifungal preparation of the present invention is to be enough to treat amount promotion antifungal the sending to infected area of fungal infection.Under the situation of tinea unguium, preparation can be applied to fingernail and/or surrounding skin.Also preparation can be applied to whole toe and/or finger tip.Preferably preparation is applied to the distal phalanx of finger or toe.Under the situation of skin infection, preparation can be applied to infected skin area.In one embodiment, local Terbinafine formulation is applied to nail surface (that is nail plate) and fingernail skin on every side.In another embodiment, use local Terbinafine formulation epidermis.

In one embodiment, this paper provides the method for treatment tinea unguium, it comprises to experimenter's local application pharmaceutical preparation, described pharmaceutical preparation comprises one or more antifungal as herein described (for example, terbinafine), lipid (preferred phospholipid) and the surfactant (preferred nonionic surfactant) for the treatment of effective dose.In another embodiment, the present invention includes the antifungal that effectively to treat the amount of tinea unguium and be delivered to the method for fingernail, it comprises to experimenter's local application pharmaceutical preparation, described pharmaceutical preparation comprises one or more antifungal as herein described (for example, terbinafine), lipid and surfactant.In certain embodiments, described method comprises, uses the as herein described local antifungal preparation combined with second kind of antifungal preparation (topical or otherwise) to the experimenter.

This paper provides the scheme of treatment human experimenter's tinea unguium, and it comprises to infected fingernail and/or infected fingernail skin histology on every side uses compositions, and described compositions comprises antifungal (for example, terbinafine), lipid and surfactant.Compositions is used the time period that crosses over 2 or more a plurality of weeks, comprised for 3,4,5,6,7,8,9,10,11,12 weeks or more of a specified duration.In one embodiment, compositions is used the time period in 10-12 week.Compositions is used a period of time, in human experimenter's infected fingernail, to produce mycology cure rate (mycological cure rate), be preferably more than about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%.

Term used herein " treatment " is meant, alleviate or improve at least in part or improve the seriousness of experimenter's disease, and/or realize at least a clinical symptoms certain alleviation, alleviate or reduce, and/or in the development of disease, exist to suppress or postpone and/or in the outbreak progress of disease or sufferer, exist to postpone.Term " treatment " also is meant, control disease state, for example tinea unguium.

By the mycology cure rate, can measure the treatment degree of tinea unguium among the experimenter.The mycology cure rate is defined as the negative microscopy of nail samples and cultivate with the feminine gender of dermatophytes in the fingernail of antifungal therapies.

The another kind of mode of determining to treat successfully is by measuring clinical cure rate.(Tavakkol waits people The American Journal of GeriatricPharmacotherapy.2006 according to disclosed method; 4:1-13), clinical cure rate can be defined as, 24 all backs toenail normal growths are 2mm and 48 week back toenail normal growth 5mm at least.

In one embodiment, topical formulations is administered to human experimenter's nail tissue and/or surrounding skin, with reach the about 1mg/g of every gram nail tissue to about 50mg/g, about 1mg/g to about 25mg/g, about 1mg/g about 5mg/g or the about 1mg/g antifungal mean concentration of about 10mg/g extremely extremely.In another embodiment, topical formulations is administered to human experimenter's nail tissue and/or surrounding skin, to reach every gram nail tissue antifungal mean concentration of 1.5mg/g, 2.0mg/g, 2.1mg/g, 2.2mg/g, 2.3mg/g, 2.4mg/g, 2.5mg/g, 2.6mg/g, 2.7mg/g, 2.8mg/g, 2.9mg/g, 3.0mg/g, 5mg/g, 10mg/g, 15mg/g, 20mg/g, 25mg/g, 30mg/g, 35mg/g, 40mg/g, 45mg/g or 50mg/g at least.In another embodiment, topical formulations is administered to human experimenter's nail tissue and/or surrounding skin, to reach every gram nail tissue about 0.1 to about 15mg/g, about 0.2 to about 12.5mg/g, about 0.5 to about 10mg/g, about 1 antifungal mean concentration to about 7.5mg/g or about 2 to about 5mg/g.1,2 or 3 weeks can be measured mean concentration after stopping to use topical formulations.

In some embodiment of described method, local antifungal preparation of the present invention use also the terbinafine average serum concentration that in the human experimenter, produces less than 10.0ng/ml, 5.0ng/ml, 4.0ng/ml, 3.0ng/ml, 2.0ng/ml, 1.0ng/ml, 0.5ng/ml or 0.2ng/ml.

In some embodiment of described method, described topical formulations comprises about 3.0mg terbinafine.For example administration every day 2 times of topical formulations.In certain embodiments, at least 3 weeks of topical formulations administration.

In yet another aspect, the invention provides the method for using topical formulations, described topical formulations comprises terbinafine, lipid and surfactant, and wherein said method comprises, topical formulations is applied to nail tissue every day 2 times, continues at least 1,2 or 3 weeks.

In some embodiment of described method, described topical formulations comprises about 0.1 to about 5.0mg, preferred 1.0 to about 5.0mg terbinafine.For example, topical formulations can comprise about 3.0mg terbinafine.

In some embodiment of described method, the terbinafine in the topical formulations is a salt form.

In yet another aspect, the invention provides the method for the fungal infection of the nail tissue for the treatment of the human experimenter, it comprises the infected nail tissue that pharmaceutical composition is administered to the human experimenter, to realize (target) every gram nail tissue about 0.1 to about 15mg/g, about 0.2 to about 12.5mg/g, about 0.5 to about 10.0mg/g, about 1.0 terbinafine mean concentrations to about 7.5mg/g or about 2.0 to about 5.0mg/g.1,2 or 3 weeks can be measured mean concentration after stopping the drug administration compositions.Use the terbinafine average serum concentration that also in the human experimenter, produces less than 10ng/mL, 5.0ng/ml, 4.0ng/ml, 3.0ng/ml, 2.0ng/ml, 1.0ng/ml, 0.5ng/ml or 0.2ng/ml.Described pharmaceutical composition comprises terbinafine, lipid and surfactant.

In some embodiment of described method, described topical formulations comprises about 1 to about 20mg antifungal.In some embodiment of described method, described topical formulations comprises about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 8mg, about 10mg, about 12mg, about 14mg, about 16mg, about 18mg or about 20mg antifungal.For example administration every day 1 time or 2 times of topical formulations.In certain embodiments, at least 3 weeks of topical formulations administration.

In some embodiment of described method, the lipid in the pharmaceutical composition is phospholipid.

In some embodiment of described method, the antifungal in the pharmaceutical composition is a salt form.In certain embodiments, a part of antifungal of certain in the pharmaceutical composition is a salt form.

In yet another aspect, the invention provides the method for the fungal infection of the nail tissue for the treatment of the human experimenter, it comprise with pharmaceutical composition be administered to the human experimenter infected nail tissue every day 2 times, continued at least 3 weeks, wherein said pharmaceutical composition comprises antifungal, lipid and surfactant.

In some embodiment of described method, described pharmaceutical composition comprises about 1 to about 20mg antifungal.For example, described pharmaceutical composition can comprise about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19 or about 20mg antifungal.

In some embodiment of described method, the terbinafine in the pharmaceutical composition is a salt form.

This paper provides the scheme of treatment human experimenter's tinea unguium in addition, it comprises the pharmaceutically acceptable preparation of dermal administration around infected fingernail and/or infected fingernail, described preparation comprises antifungal as herein described (for example, terbinafine), lipid (preferred phospholipid) and surfactant (preferred nonionic surfactant).Use described preparation a period of time, preferably cross over 2 or more a plurality of week, comprised for 3,4,5,6,7,8,9,10,11,12 weeks or more of a specified duration.In one embodiment, the time period in administered formulation 10-12 week.Use described preparation a period of time,, be preferably greater than about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% in human experimenter's infected fingernail, to produce the mycology cure rate.Perhaps, use described preparation a period of time, to prevent the recurrence of fungal infection.

When mentioning that preparation of the present invention uses, term used herein " pharmaceutically acceptable " expression, in the experimenter of its administered formulation, preparation can not produce the unacceptable irritation level.Preferably, such level is enough low, so that the suitable preparation of being ratified by administrative organization to be provided.

Used herein, reach particular result " enough amounts ", " effectively ... amount " or " be enough to ... amount " be meant, produce the amount (that is, by the administering therapeutic effective dose) of terbinafine or its salt of desirable effect (it randomly is a curative effect) effectively.In other words, " in the treatment effectively " amount is such amount, its provide at least a clinical symptoms certain alleviation, alleviate and/or reduce.With can be that those skilled in the art are well-known by the relevant clinical symptoms of the disease of method of the present invention treatment.In addition, skilled person in the art will appreciate that curative effect needs not be completely or cures, as long as provide certain benefit to the experimenter.For example, " enough amounts " or " be enough to ... amount " can be the amount of effectively treating tinea unguium, can be defined as mycology and cure.

Embodiment of the present invention can be used for antifungal preparation, application, administration and/or transportation (especially for medical science or biology purpose) enter and pass barrier and blockage (constriction), skin or fingernail such as mammalian subject (for example, people).As a result, local antifungal preparation can reach infection site with amount and the physical form that is enough to treat tinea unguium, for example nail matrix.

In certain embodiments, antifungal preparation provided herein preferably forms the surface aggregation body (ESA) of vesicle (vesicle) or other expansion, and wherein said vesicle goods have the penetrating power of passing semipermeable barrier (such as skin and/or fingernail) of raising.Although be not limited to any mechanism of action, preferred antifungal preparation can form deformability and/or the adaptive vesicle that is characterised in that them.The deformability of vesicle and/or adaptability allow vesicle to infiltrate the hole of skin and/or fingernail, and the antifungal that will be enough to treat the amount of infection is delivered to infection site.Can measure the adaptability or the deformability of vesicle at least by the ability (described hole has the average pore size than the average vesicle diameter little 50% before the infiltration) of the foraminous barrier of vesicle infiltration tool.Thereby in certain embodiments, described preparation comprises deformable vesicle, and described vesicle can infiltrate the foraminous barrier of tool, and described hole has the average pore size than the average vesicle diameter little at least 50% before the infiltration.In certain embodiments, described hole is application on human skin hole or animal skin hole.In certain embodiments, average pore diameter is about 10 microns to about 100 microns, about 30 to about 70 microns or about 40 to about 60 microns.

Use following method, can assess deformability: 1) stride barrier pressure (Δ p), measure the flux (j that aggregation or ESA suspensoid pass semipermeable membrane for what different transportation drove _a) (for example, pyknometry); 2) by with the amount of flux of each measurement force value: P (Δ p)=j divided by correspondence _a(Δ p)/Δ p, the pressure dependency of the barrier permeability P of calculating suspensoid; 3) the initial vesicle diameter of monitoring final sum 2r _Ves(Δ p)/2r _{Ves, 0}Ratio (for example passing through dynamic light scattering), 2r wherein _Ves(Δ p) is the vesicle diameter after the semipermeable barrier that Δ p drives passes, and 2r _{Ves, 0}Be initial vesicle diameter, and if necessary, set up related with flowing effect; With 4) compare data set P (Δ p) to r _Ves(Δ p)/r _{Ves, 0}, to determine the coexistence scope of high aggregation adaptability and stability.

In certain embodiments, after week, the mycology cure rate among the human experimenter is greater than about 70%, 75%, 80%, 85%, 90%, 95% or 99% at treatment about 14-week, 12-week, 10-week, 8-week, 6-week, 4-week or 2-.

In certain embodiments, after week, the clinical cure rate among the human experimenter is greater than about 70%, 75%, 80%, 85%, 90%, 95% or 99% at treatment about 48-week, 24-week, 12-week, 10-week, 8-week, 6-week, 4-week or 2-.

According to some embodiment of the inventive method, can be about 0.25mg to about 20.0mg, about 0.5mg extremely about 5.0mg, about 1.0mg, 2.0mg, 3.0mg, 4.0mg, 5.0mg, 6.0mg, 7.0mg, 8.0mg, 9.0mg, 10.0mg, 11.0mg, 12.0mg, 13.0mg, 14.0mg, 15.0mg, 16.0mg, 17.0mg, 18.0mg, 19.0mg or 20.0mg of about 10.0mg, about 0.5mg extremely in the amount of the antifungal that used to the experimenter by zone that tinea unguium influences at every turn.If desired, can be in any particular patient this amount be increased to, continues appropriate time length above 20.0mg (for example, 30,40.50,75 or 100mg).Employed about numerical value as this paper, term " about " is illustrated in the scope around the special value, and it comprises being produced by normal human error of can predicting those when measuring.For example, in certain embodiments, when use related with special value, term " about " be meant this numerical value ± 1%, ± 2%, ± 3%, ± 4%, ± 5% or ± 10%.Antifungal preparation of the present invention can administration about every day 1 time, every day 2 times, every day 3 times, every day 4 times, per 2 days 1 time, per 3 days 1 time or 1 time weekly.

In using some embodiment of local antifungal preparation provided herein, total daily dose of the antifungal that the specific part that infects to tinea unguium is used can be about 0.25mg to about 20mg, about 0.5mg to about 5mg, about 5mg about 10mg, about 10mg about 15mg or about 15mg about 20mg extremely extremely extremely.In specific embodiments, the daily dose of the antifungal of using to infection site is about 1mg, about 1.5mg, about 3mg, about 6mg, about 9mg or about 12mg.In certain embodiments, total daily dose of the antifungal of using to the experimenter be about 1mg to about 40mg, about 1mg to about 10mg, about 10mg about 20mg, about 20mg about 20mg or about 20mg about 40mg extremely extremely extremely.The daily dose of the antifungal of using in specific embodiments, to the experimenter is about 1.5mg, about 2mg, about 2.5mg, about 3mg, about 4mg, about 5mg, about 6mg, about 9mg, about 12mg, about 15mg, about 18mg, about 21mg or about 24mg.

In certain embodiments, according to the mycology cure rate, when other topical formulations of antifungal agent (for example terbinafine or itraconazole) was successfully treated infection, local antifungal preparation disclosed herein produced mycology and cures in the human experimenter.In certain embodiments, use topical formulations 14 weeks behind infected fingernail and/or surrounding skin beginning, local antifungal preparation disclosed herein shows the mycology cure rate greater than people's toe of 90%.In certain embodiments, local antifungal preparation disclosed herein produces than the higher mycology cure rate of present available local antifungal preparation.Preferred local antifungal preparation of the present invention is realized the cleaning nail growth (clean nail growth) suitable with oral terbinafine.Preferred local antifungal preparation of the present invention is realized the mycology cure rate higher than oral terbinafine.Preferred local antifungal preparation of the present invention is realized as the effective treatment rate of oral terbinafine.

In certain embodiments, local antifungal preparation disclosed herein is used for by topical antifungal non-invasively and being delivered to infection site with preponderating.Local antifungal preparation disclosed herein can substitute oral antifungal and come administration, or they can with oral antifungal administering drug combinations.Compare with the systemic concentrations of antifungal, antifungal preparation disclosed herein should produce high relatively antifungal concentration in fingernail and/or nail matrix.

Antifungal preparation disclosed herein can be more safer than oral general Terbinafine formulation.Because antifungal preparation of the present invention only is applied to infection site, the risk, gastrointestinal effects that have reduced the side effect relevant with for example oral terbinafine are (for example, be full of sense (feelings of fullness), anorexia, dyspepsia, feel sick, stomachache, diarrhoea), dermoreaction (for example, rash, urticaria), muscle skeleton reaction (arthralgia or myalgia) or sense of discomfort or fatigue.Other risk that antifungal preparation disclosed herein reduces comprises the liver enzyme and/or the liver failure of rising.

In one embodiment, the present invention includes prevention tinea unguium, the especially method of tinea unguium recurrence, it comprises that to experimenter's local application pharmaceutical preparation described pharmaceutical preparation comprises antifungal as herein described (for example, terbinafine), lipid and the surfactant for the treatment of effective dose.Antifungal preparation disclosed herein can cause low tinea unguium relapse rate in the patient.More specifically, 2 weeks after the administration, 6 weeks, 12 weeks, 24 week and 48 weeks the last time, antifungal preparation disclosed herein can have than the lower tinea unguium relapse rate of present available treatment (for example, Lan Mei express TM ointment, Lan Mei are expressed the TM lotion, Lan Mei expresses the TM gel or oral blue U.S.A expresses).

4. detailed Description Of The Invention

Generally speaking, the laboratory operation among name used herein and organic chemistry, pharmaceutical chemistry and the pharmacology as herein described is well-known, and is that this area is commonly used.Unless otherwise defined, all technology used herein and scientific terminology have the identical implication with present disclosure those of ordinary skill in the field common sense usually.

That term " alkyl " is meant straight chain or the saturated univalence hydrocarbyl of side chain (branched), wherein said alkyl can randomly be replaced by one or more substituent group Q as herein described.Except as otherwise noted, term " alkyl " also comprise straight chain and branched alkyl.In certain embodiments, alkyl is to have 1-20 (C _1-20), 1-15 (C _1-15), 1-12 (C _1-12), 1-10 (C _1-10) or 1-6 (C _1-6) the straight chain saturated mono valency alkyl of individual carbon atom, or 3-20 (C _3-20), 3-15 (C _3-15), 3-12 (C _3-12), 3-10 (C _3-10) or 3-6 (C _3-6) the saturated univalence hydrocarbyl of side chain of individual carbon atom.The C of straight chain used herein _1-6With side chain C _3-6Alkyl also is known as " low alkyl group ".The example of alkyl is including, but not limited to methyl, ethyl, propyl group (comprising all isomeric form), n-pro-pyl, isopropyl, butyl (comprising all isomeric form), normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group (comprising all isomeric form) and hexyl (comprising all isomeric form).For example, C _1-6Alkyl is meant the straight chain saturated mono valency alkyl of 1-6 carbon atom, or the saturated univalence hydrocarbyl of the side chain of 3-6 carbon atom.

Term " aryl " is meant mono-cyclic aromatic group and/or the multi-ring unit price aromatic group that contains at least one aromatic hydrocarbon ring.In certain embodiments, aryl has 6-20 (C _6-20), 6-15 (C _6-15) or 6-10 (C _6-10) individual annular atoms.The example of aryl is including, but not limited to phenyl, naphthyl, fluorenyl, azulene base, anthryl, phenanthryl, pyrenyl, biphenyl and terphenyl.Aryl also represent bicyclo-or three the ring carbocyclic rings, one of them ring is an aromatics, and other ring can be saturated, part is undersaturated or aromatics, for example, dihydro naphthyl, indenyl, indanyl or tetralyl (tetralin base).In certain embodiments, aryl also can randomly be replaced by one or more substituent group Q as herein described.

Term " heteroaryl " is meant mono-cyclic aromatic group and/or the polycyclic aromatic group that contains at least one aromatic ring, and wherein at least one aromatic ring contains the hetero atom of one or more O of being independently selected from, S and N.Each ring of heteroaryl can contain 1 or 2 O atom, 1 or 2 S atom and/or 1-4 N atom, and condition is, the heteroatomic sum in each ring is 4 or still less, and each ring contains at least 1 carbon atom.Heteroaryl can be connected on the main structure in any heteroatom or carbon atom place, causes the generation of stable compound.In certain embodiments, heteroaryl has 5-20,5-15 or 5-10 annular atoms.The example of bicyclic heteroaryl including, but not limited to: pyrrole radicals, pyrazolyl, pyrazolinyl, imidazole radicals,

Azoles base, different

Azoles base, thiazolyl, thiadiazolyl group, isothiazolyl, furyl, thienyl, Di azoly, pyridine radicals, pyrazinyl, pyrimidine radicals, pyridazinyl and triazine radical.The example of bicyclic heteroaryl is including, but not limited to indyl, benzothiazolyl, benzo Azoles base, benzothienyl, quinolyl, tetrahydro isoquinolyl, isoquinolyl, benzimidazolyl, benzopyranyl, indolizine base, benzofuranyl, isobenzofuran-base, Chromanyl (chromonyl), coumarin base (coumarinyl), cinnolines base, quinoline

Quinoline base, indazolyl, purine radicals, pyrrolopyridinyl, furo pyridine radicals, thienopyridine base, dihydro-iso indolyl and tetrahydric quinoline group.The example of tricyclic heteroaryl is including, but not limited to carbazyl, benzindole base, phenanthroline base (phenanthrollinyl), acridinyl, phenanthridinyl and xanthyl.In certain embodiments, heteroaryl also can randomly be replaced by one or more substituent group Q as herein described.

Term used herein " enoyl-" is meant-C (O)-thiazolinyl.That term " thiazolinyl " is meant straight chain or side chain univalence hydrocarbyl, it contains one or more (1-5 in one embodiment) carbon-to-carbon double bonds.Thiazolinyl can randomly be replaced by one or more substituent group Q as herein described.Term " thiazolinyl " also comprise and have " cis " and " trans " configuration (perhaps, " Z " and " E " configuration) group, as one of ordinary skill in the understanding.That term used herein " thiazolinyl " comprises straight chain and branched-chain alkenyl, except as otherwise noted.For example, C _2-6Thiazolinyl is meant the undersaturated univalence hydrocarbyl of the straight chain of 2-6 carbon atom, or the undersaturated univalence hydrocarbyl of the side chain of 3-6 carbon atom.In certain embodiments, thiazolinyl is 2-30 (C _2-30), 2-24 (C _2-24), 2-20 (C _2-20), 2-15 (C _2-15), 2-12 (C _2-12), 2-10 (C _2-10) or 2-6 (C _2-6) the straight chain univalence hydrocarbyl of individual carbon atom, or 3-30 (C _3-30), 3-24 (C _3-24), 3-20 (C _3-20), 3-15 (C _3-15), 3-12 (C _3-12), 3-10 (C _3-10) or 3-6 (C _3-6) the side chain univalence hydrocarbyl of individual carbon atom.The example of thiazolinyl is including, but not limited to vinyl, propylene-1-base, propylene-2-base, pi-allyl, cyclobutenyl and 4-methyl butene base.In certain embodiments, described enoyl-is a list-enoyl-, and it contains 1 carbon-to-carbon double bond.In certain embodiments, described enoyl-is two-enoyl-, and it contains 2 carbon-to-carbon double bonds.In certain embodiments, described enoyl-is many-enoyl-, and it contains and surpasses 2 carbon-to-carbon double bonds.

Term " heterocyclic radical " or " heterocycle " are meant the non-aromatics loop systems of monocycle and/or contain the multi-loop system of at least 1 non-aromatic ring that wherein one or more non-aromatics annular atomses are the hetero atoms that are independently selected from O, S or N; And remaining annular atoms is a carbon atom.In certain embodiments, heterocyclic radical or heterocyclic group have 3-20,3-15,3-10,3-8, a 4-7 or 5-6 annular atoms.In certain embodiments, described heterocyclic radical is monocycle, bicyclo-, three ring or tetracyclic loop systems, it can comprise the loop systems of condensed or Cheng Qiao, and wherein nitrogen or sulphur atom can be randomly oxidized, nitrogen-atoms can be randomly by quaternized, and some rings can be partially or even wholly saturated, or aromatics.Heterocyclic radical can be connected on the main structure in any heteroatom or carbon atom place, causes the generation of stable compound.The example of such heterocyclic group is including, but not limited to acridinyl, azepine

Base, benzimidazolyl, benzindole base, benzisoxa

Azoles base, benzisoxa

Piperazine base, benzo two

Alkyl, benzodioxole base, benzofuran ketone group, benzofuranyl, benzo naphtho-furan base (benzonaphthofuranyl) .alpha.-5:6-benzopyran ketone group, benzopyranyl, benzo tetrahydrofuran base, benzo tetrahydro-thienyl, diazosulfide base, benzothiazolyl, benzo thiophenyl (benzothiophenyl), benzotriazole base, benzo thiapyran base, benzo Piperazine base, benzo

Azoles base, benzothiazolyl, B-carboline base, carbazyl, Chromanyl, chromone base, cinnolines base, coumarin base, Decahydroisoquinolinpreparation base, dibenzofuran group, dihydrobenzo isothiazine base, dihydrobenzo are different

The piperazine base, the dihydrofuran base, dihydro pyranyl, dioxolanyl, the dihydro pyrazinyl, the dihydropyridine base, the pyrazoline base, the dihydro-pyrimidin base, the pyrrolin base, dioxolanyl, 1,4-dithiane base, furanonyl, furyl, imidazolidinyl, imidazolinyl, imidazole radicals, imidazopyridyl, the Imidazothiazole base, indazolyl, indolinyl, the indolizine base, indyl, different benzo tetrahydrofuran base, different benzo tetrahydro-thienyl, isobenzo-thienyl, different Chromanyl, isocoumarinyl, iso-dihydro-indole-group, isoindolyl, isoquinolyl, the isothiazole alkyl, isothiazolyl, different

Oxazolidinyl, different

Azoles base, morpholinyl, naphthyridinyl, octahydro indyl, octahydro isoindolyl,

Di azoly,

The oxazolidone base,

Oxazolidinyl,

Azoles and pyridine radicals,

Azoles base, Oxyranyle, perimidinyl, phenanthridinyl, phenanthroline base, phenarsazine base, phenazinyl, phenothiazinyl, fen

The piperazine base, phthalazinyl, piperazinyl, piperidyl, the 4-piperidone base, pteridyl, purine radicals, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridine radicals, the pyridopyridine base, pyrimidine radicals, pyrrolidinyl, pyrrolinyl, pyrrole radicals, quinazolyl, quinolyl, quinoxalinyl, quininuclidinyl, tetrahydrofurfuryl (tetrahydrofuryl), tetrahydrofuran base, tetrahydro isoquinolyl, THP trtrahydropyranyl, tetrahydro-thienyl, tetrazole radical, thiadiazoles and pyrimidine radicals, thiadiazolyl group, thio-morpholinyl, thiazolidinyl, thiazolyl, thienyl, triazine radical, triazolyl and 1,3,5-trithio piperidyl.In certain embodiments, heterocycle also can randomly be replaced by one or more substituent group Q as herein described.

Term " halogen ", " halogenide " or " halogen " are meant fluorine, chlorine, bromine and/or iodine.

Term " randomly replacement " is intended to expression, group (comprising alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclic radical) can be replaced by one or more substituent group Q, in one embodiment, replaced by 1,2,3 or 4 substituent group Q, wherein each Q is independently selected from: cyano group, halogen, oxo, nitro, C _1-6Alkyl, halo-C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _3-7Cycloalkyl, C _6-14Aryl, C _7-14Aralkyl, heteroaryl, heterocyclic radical ,-C (O) R ^e,-C (O) OR ^e,-C (O) NR ^fR ^g,-C (NR ^e) NR ^fR ^g,-OR ^e,-OC (O) R ^e,-OC (O) OR ^e,-OC (O) NR ^fR ^g,-OC (=NR ^e) NR ^fR ^g,-OS (O) R ^e,-OS (O) ₂R ^e,-OS (O) NR ^fR ^g,-OS (O) ₂NR ^fR ^g,-NR ^fR ^g,-NR ^eC (O) R ^f,-NR ^eC (O) OR ^f,-NR ^eC (O) NR ^fR ^g,-NR ^eC (=NR ^h) NR ^fR ^g,-NR ^eS (O) R ^f,-NR ^eS (O) ₂R ^f,-NR ^eS (O) NR ^fR ^g,-NR ^eS (O) ₂NR ^fR ^g,-SR ^e,-S (O) R ^e,-S (O) ₂R ^eWith-S (O) ₂NR ^fR ^g, each R wherein ^e, R ^f, R ^gAnd R ^hBe hydrogen, C independently _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _3-7Cycloalkyl, C _6-14Aryl, C _7-14Aralkyl, heteroaryl or heterocyclic radical; Or R ^fAnd R ^gThe N atom that connects with them forms heterocyclic radical.

Term " optically active " and " enantiomerism is active " the such elements collection of expression, its have be not less than about 50%, be not less than about 70%, be not less than about 80%, be not less than about 90%, be not less than about 91%, be not less than about 92%, be not less than about 93%, be not less than about 94%, be not less than about 95%, be not less than about 96%, be not less than about 97%, be not less than about 98%, be not less than about 99%, be not less than about 99.5% or be not less than about 99.8% enantiomeric excess.

When describing optically active compound, prefix R and S are used to represent the absolute configuration of molecule about its chiral centre.(+) and (-) is used to represent the optical activity of chemical compound, that is to say the direction of optically active compound rotatory polarization optical plane.(-) prefix shows that chemical compound is left-handed, that is to say, chemical compound is the rotatory polarization optical plane left or counterclockwise.(+) prefix shows that chemical compound is dextral, that is to say, chemical compound to the right or clockwise direction rotatory polarization optical plane.But the symbol (+) of optical activity and (-) are irrelevant with the absolute configuration R and the S of molecule.

Term " solvate " is meant compound or its salt provided herein, and it comprises the solvent by the bonded stoichiometric or non-stoichiometric amount of non-covalent molecular separating force in addition.At solvent is under the situation of water, and solvate is a hydrate.

Antifungal preparation provided herein comprises antifungal, lipid (preferred phospholipid), surfactant (preferred nonionic surfactant) and aqueous solution, and it has the pH of 3.5-9.0, preferred 4-7.5.Antifungal preparation provided herein can contain pharmaceutically acceptable solvate, hydrate or the salt of antifungal or antifungal.Antifungal preparation can randomly contain buffer agent, antioxidant, antiseptic, microbicide, antimicrobial and/or thickening agent.In certain embodiments, a part of antifungal of certain in the pharmaceutical composition is a salt form.

Although be not subjected to the restriction of any mechanism of action, Terbinafine formulation of the present invention preferably forms the surface aggregation body (ESA) of vesicle or other expansion, and wherein said vesicle goods have the penetrating power of passing semipermeable barrier (such as skin and/or fingernail) of raising.The surface aggregation body of vesicle of the present invention or expansion comprises terbinafine, lipid and one or more film destabilizing agents such as surfactant.

4.1. antifungal

Pharmaceutical composition disclosed herein comprises one or more antifungal.Antifungal is including, but not limited to, relevant analog, triazole and/or imidazoles, liranaftate and tolnaftate, griseofulvin and its mixture and/or combination on terbinafine, terbinafine derivant and analog, allylamine or the structure.

4.1.1. terbinafine

Terbinafine belongs to the propylamine antifungal agent.Shown in the following facial I of the structure of terbinafine:

Terbinafine can with it free alkali or salt form as the antifungal in the preparation disclosed herein.In a specific embodiment, terbinafine uses as hydrochloric acid (HCl) salt, is called terbinafine-HCl in this article.Term used herein " terbinafine " comprises the free alkali form of this chemical compound and treats and go up acceptable acid-addition salts.Suitable salt form comprises chloride, bromide, iodide, acetate and fumarate, but can use any pharmaceutically acceptable anion in principle.

The pharmaceutical preparation that contains terbinafine provided herein allows the local application terbinafine, and comprise terbinafine and at least a lipid and at least a surfactant for the treatment of effective dose, wherein said preparation comprises the 0.25-25.0% terbinafine, converts according to " total lipid " dry weight (being defined as the total dry weight of all lipids that comprise, surfactant, lipophilic excipient and medicine).The pharmaceutical preparation that contains terbinafine provided herein also can comprise 0.25-30 weight % terbinafine or about 0.5% to about 10 weight %.In specific embodiments, the pharmaceutical preparation that contains terbinafine provided herein can comprise about 0.25% to about 0.5%, about 0.5% to about 1.0%, about 1.0% to about 1.5%, about 1.5% to about 2.0%, about 2.0% to about 2.5%, about 2.5% to about 3.0%, about 3.0% to about 4.0%, about 5.0% to about 6.0%, about 6.0% to about 7.0%, about 7.0% to about 8.0%, about 8.0% to about 9.0%, about 9.0% to about 10% terbinafine, about 10% to about 12%, about 12% to about 14%, about 14% to about 16%, about 16% to about 18%, about 18% to about 20%, about 22% to about 24%, about 26%, to about 28%, about 28% to about 30% terbinafine (calculating by weight).In one embodiment, the pharmaceutical preparation that contains terbinafine comprises about 1.5% terbinafine (calculating by weight).

The pharmaceutical preparation that contains terbinafine provided herein contains the terbinafine in the amount of about 0.25mg/g to about 200mg/g scope.In certain embodiments, the amount of terbinafine can about 0.25mg/g to about 200mg/g, about 0.5mg/g to about 175mg/g, about 0.5mg/g to about 150mg/g, about 0.5mg/g to about 100mg/g, about 0.5mg/g to about 75mg/g, about 0.5mg/g about 50mg/g, about 0.5mg/g about 25mg/g, about 0.5mg/g about 20mg/g, about 0.5mg/g about 10mg/g, about 0.5mg/g about 5mg/g, about 0.5mg/g about 4mg/g, about 0.5mg/g extremely about 2mg/g and about 0.5mg/g extremely in the scope of about 1.5mg/g of about 3mg/g, about 0.5mg/g extremely extremely extremely extremely extremely extremely extremely.

The pharmaceutical preparation that contains terbinafine provided herein also comprises polar liquid medium usually.Terbinafine formulation of the present invention is used in aqueous medium usually.Terbinafine formulation of the present invention can be the form of solution, suspensoid, gel, fluid gel, Emulsion, Emulsion gel, ointment, lotion, ointment, spray, film forming solution, lacquer agent or the patch that flooded by said preparation.

4.1.2. terbinafine derivant and analog

The antifungal of pharmaceutical preparation provided herein (comprising terbinafine derivant and analog) also can comprise allylamine.In certain embodiments, terbinafine derivant or analog are the chemical compounds of formula IA,

Wherein

(a) R ¹The group of expression following formula

And R ²Expression hydrogen or low alkyl group, or R ¹And R ²The group of representing following formula together

So in formula IIa to IIi, R ⁷And R ⁸Represent independently hydrogen, halogen, trifluoromethyl, hydroxyl, nitro, low alkyl group, lower alkoxy or-C (=O)-R ¹⁵, R wherein ¹⁵Expression H, hydroxyl, low alkyl group, alkoxyl (make R ¹⁵With carbonyl is ester) or amino (make R ¹⁵With carbonyl is carbamoyl);

R ⁹Expression hydrogen, halogen, hydroxyl, low alkyl group or lower alkoxy,

X represents oxygen, sulfur, imino group, low alkyl group imino group or formula-(CH ₂) _r-group,

P is 1,2 or 3,

R is 1,2 or 3,

S is 3,4 or 5,

T is 2,3 or 4, and

V is 3,4,5 or 6;

R ³And R ⁵Represent hydrogen or low alkyl group independently, and

R ⁴Expression C _1-6Alkyl or C _3-8Cycloalkyl-(C _1-6)-alkyl; And

R ⁶The group of expression following formula

R wherein ¹¹Expression hydrogen, (C _1-6) alkyl, the alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, phenyl, benzene alkyl (phenalkyl) or the thienyl that replace of Alpha-hydroxy randomly,

R ¹², R ¹³And R ¹⁴Represent hydrogen or low alkyl group independently, and

Expression C _5-8Cycloalkylidene, its optional pair keys that contain; Or

(b) R ¹Represent as group at (a) undefined formula IIa to IIg,

R ²Expression hydrogen or low alkyl group,

R ³And R ⁴Form group-(CH together ₂) _u-, wherein u is the integer of 1-8, and

R ⁵And R ⁶Has the implication that under (a), provides.

Low alkyl group or lower alkoxy preferably have 1-4 carbon atom, especially 2 or 1 carbon atoms arbitrarily.Except as otherwise noted, moieties preferably has 1-12 carbon atom, especially 2-8 a carbon atom, an especially 2-6 carbon atom and 3-5 carbon atom most preferably, and if Cheng Qiao, then have 1-4,1 or 2 carbon atom especially.Alkenyl or alkynyl preferably has 3-6 carbon atom, an especially 3-4 carbon atom, for example pi-allyl, acrylic or propinyl arbitrarily.Such alkyl, alkoxyl, thiazolinyl and alkynyl (alkinyl) can be straight or brancheds.Preferred cycloalkylidene is a cyclohexylidene.The term cycloalkyl should be understood to comprise multi-ring group, such as bornyl or adamantyl, but preferably cyclohexyl or cyclopenta.

In specific embodiments, R ⁷And R ⁸Be identical, and all be hydrogen.In specific embodiments, R ⁹It is hydrogen or halogen.In specific embodiments, IIb and IIc and R ²And R ³The key of the carbon atom that is connected respectively with X between the position is connected and with encircle the nitrogen para-position and be connected.In specific embodiments, X is sulfur, imino group or low-grade alkyl amino.R ¹The group of formula IIb, IIc or IId or especially IIa preferably.R ²Hydrogen preferably.R ³Hydrogen preferably, and in specific embodiments, R ⁴It is alkyl.In specific embodiments, R ⁵Be hydrogen.

In specific embodiments, select the value of p, r, s, t, u and v, to produce 7-, preferred 5-or 6-unit ring.

R ⁶And the two keys between the nitrogen-atoms preferably have trans-configuration.Halogen is represented fluorine, chlorine or bromine, preferred chlorine or bromine.

In certain embodiments, the chemical compound of formula IA is as at U.S. Patent number 4,755, in 534 define, its disclosure hereby by reference integral body incorporate into.

In a specific embodiment, the chemical compound of formula IA is:

It is also referred to as terbinafine.

In a specific embodiment, the chemical compound of formula IA is:

It is also referred to as naftifine.

In a specific embodiment, the chemical compound of formula IA is:

It is described in: people such as Ryder 1992, Current Topics in Medical Mycology.Vol.4,158-188 page or leaf.

In certain embodiments, the analog of terbinafine is described in the U.S. Patent Publication No. 2007/0244336, its disclosure hereby by reference integral body incorporate into.In certain embodiments, the salt of terbinafine is described in the U.S. Patent Publication No. 2006/0004230, its disclosure hereby by reference integral body incorporate into.In certain embodiments, the antifungal allylamine derivatives is described in the U.S. Patent Publication No. 2005/0032904, its disclosure hereby by reference integral body incorporate into.

4.1.2. relevant analog on allylamine or the structure

Be suitable for analog relevant on allylamine in the local antifungal preparation provided herein or the structure including, but not limited to amorolfine, butenafine and naftifine.

In one embodiment, relevant analog is the amorolfine with following structure on allylamine in local antifungal preparation provided herein or the structure:

In another embodiment, relevant analog is the butenafine with following structure on allylamine in local antifungal preparation provided herein or the structure:

In another embodiment, relevant analog is the naftifine with following structure on allylamine in local antifungal preparation provided herein or the structure:

Analog relevant on allylamine or the structure can be used for preparation provided herein with its free alkali or its pharmaceutically acceptable solvate, hydrate or salt form.In a specific embodiment, analog relevant on allylamine or the structure uses as hydrochloric acid (HCl) salt.Term used herein " on allylamine or the structure relevant analog " comprises free alkali form and pharmaceutically acceptable solvate, hydrate or the salt form of this chemical compound.Suitable salt form is including, but not limited to chloride, bromide, iodide, acetate and fumarate.

Pharmaceutical preparation provided herein allows relevant analog on local application allylamine or the structure, and comprise relevant analog and at least a lipid and at least a surfactant on the allylamine for the treatment of effective dose or the structure, wherein said preparation comprises relevant analog on the allylamine of 0.25-25.0% or the structure, converts according to " total lipid " dry weight (being defined as the total dry weight of all lipids that comprise, surfactant, lipophilic excipient and allylamine).Preparation provided herein also can comprise relevant analog on the allylamine of 0.25-30 weight % or about 0.5% to about 10 weight % or the structure.In specific embodiments, described topical formulations can comprise about 0.25% to about 0.5%, about 0.5% to about 1%, about 1% to about 1.5%, about 1.5% to about 2%, about 2% to about 2.5%, about 2.5% to about 3%, about 3% to about 4%, about 4% to about 5%, about 5% to about 6%, about 6% to about 7%, about 7% to about 8%, about 8% to about 9%, about 9% to about 10%, about 10% to about 12%, about 12% to about 14%, about 14% to about 16%, about 16% to about 18%, about 18% to about 20%, about 22% to about 24%, about 26% to about 28%, or relevant analog (calculating by weight) on about 28% to about 30% allylamine or the structure.

Pharmaceutical preparation provided herein contains relevant analog on the allylamine of the amount of about 0.25mg/g to about 200mg/g scope or structure.In certain embodiments, the amount of relevant analog can be at about 0.25mg/g to about 200mg/g on allylamine in the pharmaceutical preparation or the structure, about 0.5mg/g is to about 175mg/g, about 0.5mg/g is to about 150mg/g, about 0.5mg/g is to about 100mg/g, about 0.5mg/g is to about 75mg/g, about 0.5mg/g is to about 50mg/g, about 0.5mg/g is to about 25mg/g, about 0.5mg/g is to about 20mg/g, about 0.5mg/g is to about 10mg/g, about 0.5mg/g is to about 5mg/g, about 0.5mg/g is to about 4mg/g, about 0.5mg/g is to about 3mg/g, about 0.5mg/g is to about 2mg/g, or about 0.5mg/g is to the scope of about 1.5mg/g.

In certain embodiments, topical formulations provided herein also comprises polar liquid medium.In certain embodiments, topical formulations provided herein is used in aqueous medium.Topical formulations provided herein can be the form of solution, suspensoid, gel, fluid gel, Emulsion, Emulsion gel, ointment, lotion, ointment, spray, film forming solution, lacquer agent or the patch that flooded by said preparation.

4.1.3. triazole and/or imidazoles

In certain embodiments, antifungal preparation disclosed herein comprises triazole and/or imidazoles, for example, has the structure of formula I:

(I)

Or single enantiomer, the mixture of its enantiomer or the mixture of diastereomer; Or pharmaceutically acceptable solvate, hydrate or its salt; Wherein:

R is C _1-12Alkyl, C _1-12Acyl group or heteroaryl-C _6-14Aryl;

X is a halogen;

Y is N or CH; And

Z is CH ₂Or O.

Radicals R among the formula I, X, Y and Z be definition in addition in this article.All combinations of the embodiment that this paper provides for these groups are all in this paper scope of the disclosure.

In certain embodiments, R is C _1-12Alkyl.In certain embodiments, R is an isopropyl.In certain embodiments, R is C _1-12Acyl group.In certain embodiments, R is an acetyl group.In certain embodiments, R is heteroaryl-C _6-14Aryl.In certain embodiments, R is 1-sec-butyl-1H-1,2,4-triazole-5 (4H)-ketone-4-base, 1-(2-hydroxyl pentane (pentan)-3-yl)-1H-1,2,4-triazole-5 (4H)-ketone-4-base or 1-((2S, 3R)-2-hydroxyl pentane-3-yl)-1H-1,2,4-triazole-5 (4H)-ketone-4-base.

In certain embodiments, each X is fluorine or chlorine independently.In certain embodiments, X is a fluorine.In certain embodiments, X is a chlorine.

In certain embodiments, Y is N.In certain embodiments, Y is CH.

In certain embodiments, Z is CH ₂In certain embodiments, Z is O.

In one embodiment, this paper provides formula I chemical compound, wherein R is isopropyl, acetyl group, 1-sec-butyl-1H-1,2, and 4-triazole-5 (4H)-ketone-4-base, 1-(2-hydroxyl pentane-3-yl)-1H-1,2,4-triazole-5 (4H)-ketone-4-base, or 1-((2S, 3R)-2-hydroxyl pentane-3-yl)-1H-1,2,4-triazole-5 (4H)-ketone-4-base; Each X is fluorine or chlorine independently; Y is N or CH; And Z is CH ₂Or O.

In one embodiment, formula I chemical compound is the itraconazole with following formula structure:

Or the mixture of single enantiomer or its diastereomer; Or its pharmaceutically acceptable solvate, hydrate or salt.

In another embodiment, formula I chemical compound is the ketoconazole with following formula structure:

Or its pharmaceutically acceptable solvate, hydrate or salt.

In another embodiment, formula I chemical compound is the posaconazole with following formula structure:

Or its pharmaceutically acceptable solvate, hydrate or salt.

In another embodiment, formula I chemical compound is the terconazole (triaconazole) with following formula structure:

Or its pharmaceutically acceptable solvate, hydrate or salt.

In another embodiment, formula I chemical compound is the SCH-50002 with following formula structure:

In another embodiment, formula I chemical compound is the Saperconazole with following formula structure:

In another embodiment, described triazole and/or imidazole antifungal agents are the fluconazol with following formula structure:

In another embodiment, described triazole and/or imidazole antifungal agents are the voriconazoles with following formula structure:

Triazole provided herein and/or imidazole antifungal agents can be used as the mixture of single enantiomer, its enantiomer or mixture or its pharmaceutically acceptable solvate, hydrate or the salt of diastereomer is used for preparation provided herein.In a specific embodiment, triazole and/or imidazole antifungal agents are with their free alkali form use.Term used herein " triazole and/or imidazole antifungal agents " comprises the free alkali form of this chemical compound, comprise mixture and the mixture of diastereomer and pharmaceutically acceptable solvate, hydrate and the salt of chemical compound of the enantiomer of single enantiomer, chemical compound, comprise its single enantiomer, the mixture of enantiomer and the mixture of diastereomer.

Pharmaceutical preparation provided herein allows local application triazole and/or imidazole antifungal agents, for example, itraconazole, ketoconazole, posaconazole, Saperconazole, SCH-50002, terconazole (triaconazole), fluconazol or voriconazole, and comprise triazole provided herein or imidazole antifungal agents and at least a lipid and at least a surfactant for the treatment of effective dose, wherein said preparation comprises the antifungal of 0.25-25%, converts according to " total lipid " dry weight (being defined as the total dry weight of all lipids that comprise, surfactant, lipophilic excipient and antifungal).Preparation provided herein also can comprise 0.25-30 weight % or about 0.5% antifungal to about 10 weight %.In specific embodiments, local antifungal preparation can comprise about 0.25% to about 0.5%, about 0.5% to about 1%, about 1% to about 1.5%, about 1.5% to about 2%, about 2% to about 2.5%, about 2.5% to about 3%, about 3% to about 4%, about 4% to about 5%, about 5% to about 6%, about 6% to about 7%, about 7% to about 8%, about 8% to about 9%, about 9% to about 10%, about 10% to about 12%, about 12% to about 14%, about 14% to about 16%, about 16% to about 18%, about 18% to about 20%, about 22% to about 24%, about 26% to about 28%, or about 28% to about 30% triazole and/or imidazole antifungal agents (calculating by weight).

Pharmaceutical preparation provided herein contains triazole and/or the imidazole antifungal agents in the amount of about 0.25mg/g to about 200mg/g scope.In certain embodiments, the amount of triazole in the pharmaceutical preparation or imidazole antifungal agents can be at about 0.25mg/g to about 200mg/g, about 0.5mg/g is to about 175mg/g, about 0.5mg/g is to about 150mg/g, about 0.5mg/g is to about 100mg/g, about 0.5mg/g is to about 75mg/g, about 0.5mg/g is to about 50mg/g, about 0.5mg/g is to about 25mg/g, about 0.5mg/g is to about 20mg/g, about 0.5mg/g is to about 10mg/g, about 0.5mg/g is to about 5mg/g, about 0.5mg/g is to about 4mg/g, about 0.5mg/g is to about 3mg/g, about 0.5mg/g is to about 2mg/g, or about 0.5mg/g is to the scope of about 1.5mg/g.

In certain embodiments, antifungal preparation provided herein also comprises polar liquid medium.In certain embodiments, antifungal preparation provided herein is used in aqueous medium.Antifungal preparation provided herein can be the form of solution, suspensoid, gel, fluid gel, Emulsion, Emulsion gel, ointment, lotion, ointment, spray, film forming solution, lacquer agent or the patch that flooded by said preparation.

Antifungal provided herein is intended to comprise all possible stereoisomer, comprises enantiomer and diastereomer and composition thereof, unless indicate specific spatial chemistry.Contain at antifungal provided herein under the situation of thiazolinyl or alkenylene, antifungal can be used as cis (Z) or trans (E) isomer or how much cis/trans (or Z/E) mixture of isomers of conduct and exists.Can pass through under the situation of low energy barrier change at constitutional isomer, the mixture that antifungal can be used as single tautomer or tautomer exists.This can be the form of the proton tautomerism in the antifungal (it contains for example imino group, ketone or oximido group); Or contain so-called valence tautomerism in the antifungal of aromatics part.Should be appreciated that single antifungal can show the isomery above a type.

Antifungal provided herein can be an enantiomer-pure, such as single enantiomer or single diastereomer, maybe can be stereomeric mixture, such as the mixture of the mixture of enantiomer, racemic mixture or diastereomer.Like this, those of skill in the art will recognize that for experience body interpolation to isomerized chemical compound, be in it (R) form chemical compound use with the using of chemical compound that is in its (S) form be equivalent.The routine techniques that is used to prepare/separate single enantiomer comprises: synthetic from suitable optically pure precursor, from the asymmetric synthesis of achirality raw material or split enantiotopic mixture, and for example chiral chromatography, recrystallization, fractionation, diastereomeric salt formation or be derivatized to diastereomeric adduct and separate then.

When antifungal provided herein contains acid or alkali part, they also can be used as pharmaceutically acceptable salt provide (referring to, people such as Berge, J.Pharm.Sci.1977,66,1-19; " Handbook of Pharmaceutical Salts, Properties, and Use, " Stahl and Wermuth, compile; Wiley-VCH and VHCA, Zurich, 2002).

The acid that is applicable to the preparation pharmaceutically acceptable salt comprises; but be not limited to: acetic acid; 2; the 2-dichloroacetic acid; the aminoacid of acidylate; fatty acid; alginic acid; ascorbic acid; the L-Aspartic Acid; benzenesulfonic acid; benzoic acid; the 4-acetaminobenzoic acid; boric acid; (+)-dextrocamphoric acid.; camphorsulfonic acid; (+)-(1S)-Camphora-10-sulfonic acid; capric acid; caproic acid; sad; cinnamic acid; citric acid; cyclamic acid; cyclohexane sulfamic acid; lauryl sulfate; ethane-1; the 2-disulfonic acid; ethyl sulfonic acid; 2-hydroxyl-ethyl sulfonic acid; formic acid; fumaric acid; galactosaccharic acid; gentisic acid; glucoheptonic acid; the D-gluconic acid; the D-glucuronic acid; L-glutamic acid; α-Yang Daiwuersuan; glycolic; hippuric acid; hydrobromic acid; hydrochloric acid; hydroiodic acid; (+)-L-lactic acid; (±)-DL-lactic acid; lactobionic acid; lauric acid; maleic acid; (-)-L MALIC ACID; malonic acid; (±)-DL-mandelic acid; methanesulfonic acid; naphthalene-2-sulfonic acid; naphthalene-1, the 5-disulfonic acid; 1-hydroxyl-2-naphthoic acid; nicotinic acid; nitric acid; oleic acid; orotic acid; oxalic acid; Palmic acid; pamoic acid; perchloric acid; phosphoric acid; the L-pyroglutamic acid; saccharic acid; salicylic acid; 4-amino-salicylic acid; decanedioic acid; stearic acid; succinic acid; sulphuric acid; tannic acid; (+)-L-tartaric acid; thiocyanic acid; p-methyl benzenesulfonic acid; undecylenic acid and valeric acid.

The alkali that is applicable to the preparation pharmaceutically acceptable salt is including, but not limited to inorganic base, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide or sodium hydroxide; And organic base, such as primary amine, secondary amine, tertiary amine and quaternary amine, aliphatic amine and aromatic amine, comprise the L-arginine, benethamine, benzathine benzylpenicillin, choline, deanol, diethanolamine, diethylamine, dimethylamine, di-n-propylamine, diisopropylamine, 2-(lignocaine)-ethanol, ethanolamine, ethamine, ethylenediamine, 2-aminopropane., N-methyl-glucamine, Hai Baming (hydrabamine), the 1H-imidazoles, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidines, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinolin, secondary amine, triethanolamine, trimethylamine, triethylamine, N-methyl D-glucamine, 2-amino-2-(methylol)-1, ammediol, and trometamol.

4.1.4. liranaftate and tolnaftate

Liranaftate is the antifungal with following formula structure:

Tolnaftate is the antifungal with following formula structure:

Liranaftate or tolnaftate can be used for preparation provided herein with its free form or its pharmaceutically acceptable solvate, hydrate or salt form.In a specific embodiment, liranaftate or tolnaftate use with its free form.Term used herein " liranaftate " comprises free form and pharmaceutically acceptable solvate, hydrate or the salt form of this chemical compound.Term used herein " tolnaftate " comprises free form and pharmaceutically acceptable solvate, hydrate or the salt form of this chemical compound.

Pharmaceutical preparation provided herein allows local application liranaftate or tolnaftate, and comprise liranaftate or tolnaftate and at least a lipid and at least a surfactant for the treatment of effective dose, wherein said preparation comprises liranaftate or the tolnaftate of 0.25-25%, converts according to " total lipid " dry weight (being defined as the total dry weight of all lipids that comprise, surfactant, lipophilic excipient and liranaftate or tolnaftate).Preparation provided herein also can comprise the liranaftate or the tolnaftate of 0.25-30 weight % or about 0.5% to about 10 weight %.In specific embodiments, described topical formulations can comprise about 0.25% to about 0.5%, about 0.5% to about 1%, about 1% to about 1.5%, about 1.5% to about 2%, about 2% to about 2.5%, about 2.5% to about 3%, about 3% to about 4%, about 4% to about 5%, about 5% to about 6%, about 6% to about 7%, about 7% to about 8%, about 8% to about 9%, about 9% to about 10%, about 10% to about 12%, about 12% to about 14%, about 14% to about 16%, about 16% to about 18%, about 18% to about 20%, about 22% to about 24%, about 26% to about 28%, or about 28% to about 30% liranaftate or tolnaftate (calculating by weight).

Pharmaceutical preparation provided herein contains liranaftate or the tolnaftate in the amount of about 0.25mg/g to about 200mg/g scope.In certain embodiments, the amount of liranaftate in the pharmaceutical preparation or tolnaftate can be at about 0.25mg/g to about 200mg/g, about 0.5mg/g is to about 175mg/g, about 0.5mg/g is to about 150mg/g, about 0.5mg/g is to about 100mg/g, about 0.5mg/g is to about 75mg/g, about 0.5mg/g is to about 50mg/g, about 0.5mg/g is to about 25mg/g, about 0.5mg/g is to about 20mg/g, about 0.5mg/g is to about 10mg/g, about 0.5mg/g is to about 5mg/g, about 0.5mg/g is to about 4mg/g, about 0.5mg/g is to about 3mg/g, about 0.5mg/g is to about 2mg/g, or about 0.5mg/g is to the scope of about 1.5mg/g.

4.1.5. griseofulvin

Griseofulvin is the antifungal with following formula structure:

Griseofulvin can be used for preparation provided herein with its free form or its pharmaceutically acceptable solvate, hydrate or salt form.In a specific embodiment, griseofulvin uses with its free form.Term used herein " griseofulvin " comprises free form and pharmaceutically acceptable solvate, hydrate or the salt form of this chemical compound.

Pharmaceutical preparation provided herein allows the local application griseofulvin, and comprise griseofulvin and at least a lipid and at least a surfactant for the treatment of effective dose, wherein said preparation comprises the griseofulvin of 0.25-25%, converts according to " total lipid " dry weight (being defined as the total dry weight of all lipids that comprise, surfactant, lipophilic excipient and griseofulvin).Preparation provided herein also can comprise 0.25-30 weight % or about 0.5% griseofulvin to about 10 weight %.In specific embodiments, local Gris-PEG can comprise about 0.25% to about 0.5%, about 0.5% to about 1%, about 1% to about 1.5%, about 1.5% to about 2%, about 2% to about 2.5%, about 2.5% to about 3%, about 3% to about 4%, about 4% to about 5%, about 5% to about 6%, about 6% to about 7%, about 7% to about 8%, about 8% to about 9%, about 9% to about 10%, about 10% to about 12%, about 12% to about 14%, about 14% to about 16%, about 16% to about 18%, about 18% to about 20%, about 22% to about 24%, about 26% to about 28%, or about 28% to about 30% griseofulvin (calculating by weight).

Pharmaceutical preparation provided herein contains the griseofulvin in the amount of about 0.25mg/g to about 200mg/g scope.In certain embodiments, the amount of the griseofulvin in the pharmaceutical preparation can be at about 0.25mg/g to about 200mg/g, about 0.5mg/g is to about 175mg/g, about 0.5mg/g is to about 150mg/g, about 0.5mg/g is to about 100mg/g, about 0.5mg/g is to about 75mg/g, about 0.5mg/g is to about 50mg/g, about 0.5mg/g is to about 25mg/g, about 0.5mg/g is to about 20mg/g, about 0.5mg/g is to about 10mg/g, about 0.5mg/g is to about 5mg/g, about 0.5mg/g is to about 4mg/g, about 0.5mg/g is to about 3mg/g, about 0.5mg/g is to about 2mg/g, or about 0.5mg/g is to the scope of about 1.5mg/g.

In certain embodiments, Gris-PEG provided herein also comprises polar liquid medium.In certain embodiments, Gris-PEG provided herein is used in aqueous medium.Gris-PEG provided herein can be the form of solution, suspensoid, gel, fluid gel, Emulsion, Emulsion gel, ointment, lotion, ointment, spray, film forming solution, lacquer agent or the patch that flooded by said preparation.

4.2. lipid

On meaning of the present invention, " lipid " is its arbitrary substance with the character that resembles or be similar to fat.Usually, it has the non-polar group of expansion (" chain " X), and also has water miscible, polar hydrophilic segment usually, and promptly " head " base (Y) and has basic formula II.

X-Y _n(II)

Wherein n is equal to or greater than 0.The lipid of n=0 is called nonpolar lipid, and the lipid of n 〉=1 is called polarity lipid.On this meaning, all amphiphilic substances (comprise, but be not limited to glyceride type, phosphoglycerol lipid, glycerol phosphonic acid ester (glycerophosphinolipids), glycerol phosphono lipid (glycerophosphonolipids), sulfolipins, sphingolipid, isoprenoid lipid, steroid class or sterols and contain the lipid of carbohydrate) can be called lipid usually, and thereby comprise in the present invention.EP 0 475 160 A1 (referring to, for example the 4th, 1.8 page to the 6th, 1.3 page) and U.S. Patent number 6,165,500 (referring to, for example the 6th, 1.10 row are to the 7th, 1.58 row) in the tabulation definition relevant with lipid of relevant lipid is provided, they incorporate this paper by reference into.

Phospholipid is the chemical compound of formula III for example:

R ¹-CH ₂-CHR ²-CR ³H-O-PHO ₂-O-R ⁴(III)

R wherein ¹And R ²Can not be hydrogen, OH or C ₁-C ₃Alkyl, and be aliphatic chain independently usually, the most often be derived from fatty acid or aliphatic alcohol.R ³Hydrogen normally.The OH-group of phosphate ester is hydroxyl or hydroxyl anion (that is, hydroxide) form, and this depends on the Ionized degree of group.In addition, R ⁴Can be proton or the short-chain alkyl that replaced by three short-chain alkyl ammoniums (such as the trimethylammonium group), or the short-chain alkyl of amino-replacement, lack alkyl such as 2-trimethylammoniumethyl (choline base) or 2-dimethylammonium.

Sphingophospholipid is the chemical compound of formula III B for example:

R ¹-sphingol-O-PHO ₂-O-R ⁴(IIIB)

R wherein ¹Be to be connected to fatty acid on the nitrogen of sphingol and R by amido link ⁴Has the implication that under formula III, provides.

Lipid is the material of formula III or IIIB preferably, wherein R ¹And/or R ²Be acyl group or alkyl, positive hydroxyl acyl group or positive hydroxy alkyl, but also can be side chain that one or more methyl are connected the almost arbitrfary point of chain; Usually, methyl is near chain end (XOR anteiso-).In addition, radicals R ¹And R ²Can be saturated or unsaturated (single-, two-or many-undersaturated).R ³Be hydrogen, and R ⁴Be 2-trimethylammoniumethyl (headgroup of the corresponding phosphatldylcholine of the latter), 2-dimethylammonium ethyl, 2-first QAE quaternary aminoethyl or 2-amino-ethyl (corresponding PHOSPHATIDYL ETHANOLAMINE headgroup).R ⁴Also can be that proton (providing phosphatidic acid), serine (providing Phosphatidylserine), glycerol (providing phosphatidyl glycerol), inositol (providing phosphatidylinositols) or alkyl amine group are (under the situation of ethamine, provide PHOSPHATIDYL ETHANOLAMINE), if select to use naturally occurring phosphoglyceride.Otherwise, can consider that also other enough polar phosphate ester (make and will form lipid bilayer) is used to prepare preparation of the present invention arbitrarily.

Table 1 has been listed according to preferred phospholipid of the present invention.

In the context of the present invention, base of optimum selection lipid is uncharged, and forms bilayer stable, well-hydrated; Phosphatidylcholine and sphingomyelins are the most outstanding representatives of such lipid.They any can have the chain of in table 1, listing, those that form mobile phase bilayer (wherein the fat chain is in disordered state) are preferred.

Also different electronegative (that is, anionic) lipid can be mixed in the vesicle lipid bilayer, to regulate loading or the fat aggregation release from obtain of (cationic) medicine in the lipid aggregation.The attractive example of charged lipid like this is phosphatidyl glycerol, phosphatidylinositols and less preferred a little phosphatidic acid (with its Arrcostab) or Phosphatidylserine.Any technical staff of this area can recognize, unites with electroneutral double-deck component and uses them to compare, and not too recommends only to prepare vesicle from charged lipid.Using under the situation of charged lipid, must select buffer to form and/or the pH nurse, so that guarantee the medicine of oppositely charged of the lipid headgroup degree of ionization of wishing and/or hope and the electrostatic interaction degree between the lipid molecule.In addition, the same with neutral lipid, charged double-deck lipidic component can have any chain of listing in principle in table 1.But, the effect that increases along with aliphatic chain is mobile owing to the vesicle adaptability, also owing to lipid in mobile phase each other and with the blended better ability of medicine, the chain of formation mobile phase lipid bilayer obviously is preferred.

In the basic aliphatic chain type that following table provides, select fatty acid-or aliphatic alcohol-deutero-lipid chain usually:

Table 2:(is) base of optimum selection, straight, saturated aliphatic chain residue

Table 3:(is) preferred monoene aliphatic chain residue

Table 4:(is) preferred diene and polyenoid aliphatic chain residue

Other pair key combination or position also are possible.

In addition, suitable fatty residue can be a side chain, for example, can contain at the anti-ectopic methyl of the XOR of fatty acid chain, or nearer in the middle of chain, as in 10-R-methyl octadecanoid acid or tuberlostearic acid chain.In branched chain fatty acid, important relatively still isoprenoid wherein manyly is derived from 3,7,11,15-tetramethyl 16 carbon-trans-2-alkene-1-alcohol, promptly chlorophyllous aliphatic alcohol part.Example comprises 5,9,13,17-tetramethyl octadecanoid acid, especially 3,7,11,15-tetramethyl hexadecanoic acid (phytanic acid) and 2,6,10,14-tetramethyl-pentadecane acid (pristanic acid).4,8, the good source of 12-trimethyl tridecanoic acid is the ocean organism.The combination of the side chain on two keys and the fatty residue also is possible.

Perhaps, suitable fatty residue can be carried one or several oxygen-or cyclic group, especially at middle-of-chain or towards end.In up-to-date alicyclic ring fatty acid, the most outstanding is comprises those of cyclopropane (with cyclopropylene sometimes) ring, but also can see cyclohexyl and suberyl ring, and may be used for purpose of the present invention.2-(D)-hydroxy aliphatic acid ratio alicyclic ring fatty acid is ubiquity more, and also is the important component of sphingolipid.Also interested is 15-hydroxyl-hexadecanoic acid and 17-hydroxyl-octadecanoid acid and possible 9-hydroxyl-18-anti-form-1 0, anti-form-1 2-diene (dimorphecolic) and 13-hydroxyl-18-cis-9, anti-form-1 1-diene (coriolic) acid.Can argue ground, at present the most outstanding medicinal hydroxyl-fatty acid be castor oil acid, (D-(-) 12-hydroxyl-18-cis-9-olefin(e) acid, its account for Oleum Ricini up to 90%, it also often uses with hydrogenated form.Epoxy-methoxyl group-only have limited actual interest in the context of the present invention with class furan-fatty acid.

Generally speaking, unsaturated, the branch (branching) of fatty acid or the derivatization of any other type are the most compatible with purpose of the present invention, and the position of these modifications is in fatty acid middle-of-chain or end portion.Cis-unsaturated fatty acid also is more preferred than trans-undersaturated fatty acid, and the fat group that has still less two keys than have a plurality of pairs of keys those more preferably, this is because the latter's oxidation sensitive.In addition, symmetrical chain lipid is fit to better than asymmetric chain lipid usually.

Preferably the lipid of formula III is, for example, natural phosphatidylcholine, it is called lecithin in the past.It can (be rich in Palmic acid, C from egg _16:0With oleic acid, C _18:1Group, but stearic acid, C also comprised _18:0, palmitoleic acid, C _16:1, linolenic acid, C _18:2With arachidonic acid, C _20:4Group), Semen sojae atricolor (is rich in undersaturated C ₁₈Chain, but also contain some Palmic acid groups, and other group on a small quantity), Cortex cocois radicis (being rich in saturated chain), Fructus Canarii albi (being rich in single unsaturated chain), Stigma Croci (Flos Carthami) and Helianthi (being rich in the n-6 linoleic acid), Semen Lini (being rich in the n-3 linolenic acid), blubber fat (being rich in monounsaturated n-3 chain), primrose or cyclamen (being rich in the n-3 chain) obtain.Preferred natural PHOSPHATIDYL ETHANOLAMINE (being called cephalin in the past) is egg-derived or Semen sojae atricolor often.Biogenetic preferred sphingomyelins is usually from egg or cerebral tissue preparation.Preferred Phosphatidylserine also is derived from the brain material usually, and phosphatidyl glycerol perhaps by changeing the phospholipid acidylate, uses Choline phosphatase to prepare from native phosphatidylcholine preferably from extracting such as antibacterials such as escherichia coli.Preferably the phosphatidylinositols that uses separates from commercial soybean phospholipid or Hepar Bovis seu Bubali extract.Preferred phosphatidic acid extracts certainly above-mentioned source arbitrarily, or uses Choline phosphatase from suitable phosphatidylcholine preparation.

In addition, the synthetic phosphatldylcholine (R in formula III ⁴And R corresponding 2-trimethylammoniumethyl), ¹And R ²Be the aliphatic chain as defining in the paragraph in front, it has 12-30 carbon atom, preferred 14-22 carbon atom, more preferably 16-20 carbon atom, and condition is, necessary selection chain, thus guarantee that the ESA that obtains comprises mobile lipid bilayer.This typically refers to and uses shorter saturated chain and relative longer unsaturated chain relatively.Synthetic sphingomyelins (the R in formula III B ⁴And R corresponding 2-trimethylammoniumethyl), ¹Be aliphatic chain as defining in the paragraph in front, each fully saturated chain have 10-20 carbon atom, preferred 10-14 carbon atom, and each unsaturated chain has 16-20 carbon atom.

Synthetic PHOSPHATIDYL ETHANOLAMINE (R ⁴Be the 2-amino-ethyl), synthetic phosphatidic acid (R ⁴Be proton) or its ester (R ⁴Correspondence is short-chain alkyl for example, such as methyl or ethyl), synthetic Phosphatidylserine (R ⁴Be L-or D-serine) or synthetic phosphatidyl (gathering) alcohol such as phosphatidylinositols, phosphatidyl glycerol (R ⁴Be L-or D-glycerol) be preferred lipid, wherein R ¹And R ²Be the identical or appropriate different type and the fatty residue of length, especially such as provide in the correspondence table that provides at preamble those.In addition, R ¹Can represent thiazolinyl and R ²Equal hydroxy alkyl, such as myristyl hydroxyl or cetyl hydroxyl, for example, and in two myristyls or double hexadecyl phosphatldylcholine or ethanolamine, R ¹Can represent thiazolinyl, and R ²Expression hydroxyl acyl group is such as plasmalogen (R ⁴Or R trimethylammoniumethyl), ¹Can be acyl group, such as lauryl, myristoyl or palmityl, and R ²Can represent hydroxyl, for example, in natural or synthetic haemolysis phosphatldylcholine or lysophosphatidyl glycerol or lysophosphatidyl ethanolamine, such as 1-myristoyl or 1-palmityl haemolysis phosphatldylcholine or-PHOSPHATIDYL ETHANOLAMINE; Frequently, R ³Expression hydrogen.

In implication of the present invention, the lipid of formula III B also is suitable lipid.In formula III B, n=1, R ¹Be thiazolinyl, R ²Be acyl group acylamino-group, R ³Be hydrogen, and R ⁴Expression 2-trimethylammoniumethyl (choline group).The known sphingomyelins that is named as of such lipid.

In addition; suitable lipid is that haemolysis phosphatldylcholine analog is such as 1-lauroyl-1; 3-dihydroxypropane-3-PC, monoglyceride such as monoolein or myristic acid monoglyceride, cerebroside, ceramide polyhexoside, sulfatide, sheath plasmalogen, ganglioside or glyceride, it is at 3 phosphoryl or phosphono or phosphino-s that do not contain free or esterification.An example of such glyceride is two acyl glycerides or the 1-thiazolinyl-1-hydroxyl-2-acyl glyceride that contains any acyl group or thiazolinyl; wherein the 3-hydroxyl is by one of carbohydrate group etherificate; described carbohydrate group can be mentioned for example galactosyl, such as single galactosyl glycerol.

Also can be by biochemical mode, form from natural or synthetic precursor and to have the headgroup of hope or the lipid of chain base character, for example, by means of phospholipase (such as E.C. 3.1.1.32, A2, B, C and especially D), desaturase, prolongation enzyme, acyltransferase etc.

In addition, suitable lipid is lipid arbitrarily, and it is included in the biomembrane, and can extract down such as non-polar organic solvents such as chloroform are auxiliary.Except the lipid of having mentioned, such lipid also comprises, for example, steroid class such as estradiol or sterols such as cholesterol, cupreol, desmosterol, 7-ketone-cholesterol or beta-cholestanol, fatsoluble vitamin such as V-A acidic, vitamin such as retinol1 or A2, vitamin E, vitamin K such as vitamin K1 or K2 or vitamin D1 or D3 etc.

The amphiphilic component that dissolubility is lower comprises; or preferably include; synthetic lipid is such as myristoleoyl; palmitoleoyl; petroselinyl; petroselaidyl; oleoyl; elaidyl; cis-or trans-vaccenoyl; inferior oleoyl; Caulis et Folium Lini acyl group; linolaidyl; the stearidonic acyl group; gondoyl; the eicosylene acyl group; 20 carbon, two enoyl-s; 20 carbon, three enoyl-s; the arachidonic acyl group; cis-or trans-two dodecylene acyl groups; 22 carbon, two enoyl-s; 22 carbon, three enoyl-s; 22 carbon tetraene acyl groups; lauroyl; tridecanoyl; myristoyl; pentadecanoyl; palmityl; 17 carbonic acyl radicals; stearoyl or 19 carbonic acyl radicals; phosphoglyceride; or has a corresponding derivant of side chain; or corresponding dialkyl group or sphingol derivant; glycolipid or other diacyl or dialkyl group lipid.

The amphiphilic component that dissolubility is higher often is derived from the lower component of listing above of dissolubility; and in order to increase dissolubility; replaced and/or compound and/or combination by following radicals: bytyry, valeryl, caproyl, heptanoyl group, caprylyl, pelargonyl group, capryl or undecanoyl substituent group; or the substituent group of several separate selections, or improve the different material of dissolubility.

Other suitable lipid is diacyl-or poly-inferior ethoxyl (ethoxylene) derivant of dialkyl group-phosphoglycerol ethanolamine azo, two capryl phosphatldylcholines or diacylphosphoolligomaltobionamide.

In certain embodiments, the amount of lipid is about 1% to about 10%, about 2% to about 10%, about 1% to about 4%, about 4% to about 7% or about 7% to about 10% (calculating by weight) in the preparation.In a specific embodiment, described lipid is phospholipid.In another specific embodiment, described lipid is phosphatidylcholine.In one embodiment, topical formulations of the present invention contains one or more antifungal (for example, terbinafine), phosphatidylcholine and surfactant, and wherein said preparation contains the phosphatidylcholine of 1-10 weight %.

4.3. surfactant

Term " surfactant " has its common implication.The definition that the tabulation of relevant surfactant is relevant with surfactant, be provided at EP 0 475 160 A1 that incorporate this paper by reference into (referring to, for example the 6th, l.5 page or leaf is to the 14.1.17 page or leaf) and U.S. Patent number 6,165,500 (referring to, for example the 7th, 1.60 row are to the 19th, 1.64 row) in, in suitable surfactant or pharmacy handbook, such as Handbook of Industrial Surfactants or American Pharmacopeia, European Pharmacopoeia.In certain embodiments of the invention, surfactant is those that describe in the table 1-18 of U.S. Patent Application Publication No. 2002/0012680A1, and this patent disclosure is open on January 31st, 2002, its disclosure hereby by reference integral body incorporate into.Therefore, following tabulation only is provided in the practice of present patent application common or useful several surfactant-based other and selects, and it never is complete or exclusive.Want preferred surfactants used according to the invention to comprise to have greater than those of 12 HLB.This tabulation comprises Ionized long-chain fatty acid or long-chain fatty alcohol, long-chain fat ammonium salt such as alkyl-or enoyl--trimethyl-,-dimethyl-and-methyl-ammonium salt, alkyl-or enoyl--sulfate, long aliphatic chain dimethyl-amino oxide such as alkyl-or enoyl--dimethyl-amino oxide, long aliphatic chain is alkanoyl for example, dimethyl-amino oxide and especially lauryl dimethyl-amino oxide, long aliphatic chain is alkyl-N-methyl glucose amide (glucamide) and alkanoyl-N-methyl glucose amide for example, such as MEGA-8, MEGA-9 and MEGA-10, long aliphatic chain-the N of N-, the N-dimethylglycine, N-alkyl-N for example, the N-dimethylglycine, 3-(long aliphatic chain-dimethylammonio)-alkane-sulphonic acid ester, 3-(acyl group dimethylammonio)-alkane sulfonic acid ester for example, the long aliphatic chain derivant of sulfosuccinate is such as two (2-ethyl alkyl) sulfosuccinate, long aliphatic chain-sulfobetaines, acyl group-sulfobetaines for example, long aliphatic chain betanin, such as EMPIGEN BB or ZWITTERGENT-3-16,-3-14,-3-12,-3-10 or-3-8, or polyethylene-ethylene glycol-acyl group phenyl ether, especially nine ethylene-ethylene glycol-octyl group-phenyl ether, polyethylene-long aliphatic chain-ether, especially polyethylene-acyl group ether, such as nine ethylene-decyl ethers, nine ethylene-lauryl ether or eight ethylene-lauryl ether, polyethylene glycol-different acyl group ether, such as eight vinyl ethylene glycol-different three decyl ethers, polyethylene glycol-sorbitan-long aliphatic chain ester, for example polyethylene glycol-sorbitan-acyl ester and especially polyoxyethylene-monolaurate (for example polysorbate 20 or polysorbas20), polyoxyethylene-sorbitan-monoleate (for example polyoxyethylene sorbitan monoleate or Tween 80), polyoxyethylene-sorbitan-single lauroleylate, polyoxyethylene-sorbitan-single octadecane acid esters (petroselinate), polyoxyethylene-sorbitan--single vaccenic acid acid esters (elaidate), polyoxyethylene-sorbitan-macene acid esters, polyoxyethylene-sorbitan-palmitoleinylate, polyoxyethylene-sorbitan-right-etroselinylate, poly-hydroxyl ethylene-long aliphatic chain ether, for example poly-hydroxyl ethylene-acyl group ether, such as poly-hydroxyl ethylene-lauryl ether, poly-hydroxyl ethylene-myristoyl ether, poly-hydroxyl ethylene-cetyl stearoyl, poly-hydroxyl ethylene-palmityl ether, poly-hydroxyl ethylene-oleoyl ether, poly-hydroxyl ethylene-palmitoleoyl ether, poly-hydroxyl ethylene-Caulis et Folium Lini base, poly-hydroxyl ethylene-4, or 6, or 8, or 10, or 12-lauryl, myristoyl (miristoyl), palmityl, palmitoleoyl (palmitoleyl), oleoyl or inferior oleoyl (linoeyl) ether (Brij series), or corresponding ester, poly-hydroxyl ethylene-laurate,-myristinate,-cetylate,-stearate or-oleate, especially poly-hydroxyl ethylene-8-stearate (Myrj 45) and poly-hydroxyl ethylene-8-oleate, the Oleum Ricini 40 of polyethoxylated (floating (cremophor) EL of breast), the long aliphatic chain of sorbitan-list, alkylates (Arlacel or span series) for example, especially (Arlacel 20 for sorbitan-monolaurate, span 20), long aliphatic chain, acyl group-N-methyl glucose amide for example, alkanoyl-N-methyl glucose amide, especially capryl-N-methyl glucose amide, dodecanoyl-N-methyl glucose amide, long aliphatic chain sulfuric ester, alkyl-sulfuric ester for example, alkyl sulfate is such as lauryl-sulfuric ester (SDS), oleoyl-sulfuric ester; Long aliphatic chain thioglucose glycoside, such as alkylthio group portugal glycoside and especially heptyl-, octyl group-and nonyl-β-D-sulfur Glucopyranose. glycoside; Long aliphatic chain derivant, especially alkyl-portugal glycoside and the maltoside of different carbohydrates (such as pentose, hexose and disaccharide), such as hexyl-, heptyl-, octyl group-, nonyl-and decyl-β-D-pyranglucoside or D-maltoside; Other salt; especially sodium salt; cholate; dexycholate; glycocholate; glycocholeic acid salt; taurodeoxycholate; taurocholate; soap; especially oleate; vaccenic acid hydrochlorate (elaidate); linoleate; laruate; or myristate; the most common na form; the plain class of lysophosphatide; positive eight decene-phosphoglyceride acid; eight decene-phosphoryl glycerol; eight decene-phosphoryl serine; just long aliphatic chain-glycerol-phosphatidic acid; such as positive acyl group-glycerol-phosphatidic acid; especially lauryl glycerol-phosphatidic acid; oleoyl-glycerol-phosphatidic acid; just long aliphatic chain-phosphoryl glycerol; such as positive acyl group-phosphoryl glycerol; especially lauryl-; myristoyl-; oleoyl-or palmitoleoyl-phosphoryl glycerol; just long aliphatic chain-phosphoryl serine; such as positive acyl group-phosphoryl serine; especially lauryl-; myristoyl-; oleoyl-or palmitoleoyl-phosphoryl serine; n-tetradecane base-glycerol-phosphatidic acid; n-tetradecane base-phosphoryl glycerol; n-tetradecane base-phosphoryl serine; corresponding-; vaccenic acid acyl (elaidoyl)-; the plain class of vaccenyl-lysophosphatide; corresponding short-chain phospholipid, and all surface is active and thereby make the unsettled polypeptide of film.Usually option table surface-active agent chain is in flow regime, or compatible with keeping of mobile chain state in the vector aggregation body at least.

Table 5 has been listed according to preferred surfactant of the present invention.

In certain embodiments, surfactant is a nonionic surfactant.Surfactant can be present in the preparation to about 10% (calculating by weight) with about 1% to about 10%, about 1% to about 4%, about 4% to about 7% or about 7%.In certain embodiments, nonionic surfactant is selected from: polyoxyethylene sorbitan (Polysorbate surfactant), poly-hydroxyl ethylene stearate (polyhydroxyethylene stearate) or poly-hydroxyl ethylene lauryl ether (polyhydroxyethylene laurylether) (Brij surfactant).In a specific embodiment, surfactant is polyoxyethylene-sorbitan-monoleate (for example polyoxyethylene sorbitan monoleate or a Tween 80).

4.4. preparation

Antifungal preparation of the present invention can contain the antifungal of 1-10 weight %, 1-15 weight %, 1-20 weight % or 1-30 weight %.Local antifungal preparation of the present invention can contain the lipid of 1-10 weight %, 1-15 weight %, 1-20 weight % or 1-30 weight %.Antifungal preparation of the present invention can contain the surfactant of 1-10 weight %, 1-15 weight %, 1-20 weight %, 1-30 weight %, 1-40 weight % or 1-50 weight %.

Antifungal preparation of the present invention can have the lipid of certain limit and the ratio of surfactant.This ratio can be represented (mol lipid/mol surfactant) according to the mode of mol ratio.The lipid in the antifungal preparation of the present invention and the mol ratio of surfactant can be about 1: 2 to about 10: 1.In certain embodiments, described ratio is about 1: 1 to about 5: 1, about 1: 1 to about 2: 1, about 2: 1 to about 3: 1, about 3: 1 to about 4: 1, about 4: 1 to about 5: 1 or about 5: 1 to about 10: 1.In specific embodiments, the ratio of lipid and surfactant is about 1.0: 1.0, about 1.25: 1.0, about 1.5/1.0, about 1.75/1.0, about 2.0/1.0, about 2.5/1.0, about 3.0/1.0 or about 4.0/1.0.

Antifungal preparation of the present invention can have the antifungal of variation and the ratio of lipid.This ratio can be represented (mol antifungal/mol lipid) according to the mode of mol ratio.The antifungal in the local antifungal preparation of the present invention and the mol ratio of lipid can be about 0.2: 1 to about 2: 1.In certain embodiments, described ratio is about 0.2: 1 to about 0.7: 1, about 0.7: 1 to about 1.2: 1, about 1.2: 1 to about 1.7: 1 or about 1.7: 1 to about 2: 1.

Antifungal preparation of the present invention also can have the total amount (TA) of following 3 kinds of components of the amount of variation: the antifungal of combination, lipid and surfactant.TA amount can be represented with the mode of the percentage by weight of total composition.In one embodiment, described TA is about 1% to about 40%, about 5% to about 30%, about 7.5% to about 15%, about 5% to about 10%, about 10% to about 20% or about 20% to about 30%.In specific embodiments, described TA is 8%, 9%, 10%, 15% or 20%.

Total fat amount of selecting for local antifungal preparation of the present invention, lipid/surfactant have been described than (mol/mol) and antifungal/surfactant scope below in the table 6 than (mol/mol):

Table 6: the ratio of the ratio of total lipid, lipid and surfactant and antifungal and lipid

Antifungal preparation of the present invention can randomly contain one or more following compositions: cosolvent, chelating agen, buffer agent, antioxidant, antiseptic, microbicide, softening agent, wetting agent, lubricant and thickening agent.The preferred amounts of optional components is as shown in table 7.

Antifungal preparation of the present invention can comprise buffer agent, transfers to the scope of pH3.5-pH 9, pH 4-pH 7.5 or pH 4-pH 6.5 with the pH with aqueous solution.The example of buffer agent is including, but not limited to acetate buffer, lactate buffer agent, phosphate buffer and propionate buffer agent.

Antifungal preparation of the present invention is prepared in aqueous medium usually.Can with or without cosolvent (such as lower alcohol) formulated.

Usually adding " microbicide " or " antimicrobial " reduces the bacterial population in the pharmaceutical preparation.Some examples of microbicide are: short chain alcohol comprises ethyl and isopropyl alcohol, chlorobutanol, benzyl alcohol, chlorobenzene methanol, dichlorbenzyl alcohol, hexachlorophene; Phenolic compounds, for example between cresol, 4-chloro--cresol, right-chloro-between-xylenols, dichlorophen, hexachlorophene, povidone iodine; Parabens, especially alkyl-parabens, for example methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, P-hydroxybenzoic acid benzene methyl; Acids, for example sorbic acid, benzoic acid and salt thereof; Quaternary ammonium compound, for example alkylammonium (alkonium) salt, for example bromide, zephiran salt, for example chloride or bromide, hexadecane trimethyl ammonium (cetrimonium) salt, for example, bromide, phenol hydrocarbon ammonium (phenoalkecinium) salt, for example domiphen bromide, cetylpyridinium chloride and other salt; In addition, compound containing mercury, for example phenylmercuric acetate, phenylmercuric borate or phenylmercuric nitrate, thimerosal, chlorhexidine or its gluconate; Or have the biogenetic derivation chemical compound of antibacterial activity or the mixture of their any appropriate arbitrarily.

The example of " antioxidant " is: BHA (BHA), butylated hydroxytoluene (BHT) and two-tert-butyl phenol (LY178002, LY256548, HWA-131, BF-389, CI-986, PD-127443, E-5119, BI-L-239XX etc.), tertiary butylated hydroquinone (TBHQ), propyl gallate (PG), 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ); Arylamine (for example diphenylamines, right-alkylthio group-neighbour-anisidine, ethylene diamine derivative, carbazole, tetrahydroindene diindyl); Phenol and phenolic acid (guaiacol, hydroquinone, vanillin, gallic acid and ester thereof, protocatechuic acid, quinic acid, syringic acid, ellagic acid, salicylic acid, nordihydroguaiaretic acid (NDGA), eugenol); Tocopherol (comprise tocopherol (α, β, γ, δ) and derivant thereof, for example acidylate tocopherol (as-acetate ,-laurate ,-myristinate ,-cetylate ,-oleate ,-linoleate etc. or any other suitable tocopherol-fatty acid ester), tocopherol-POE-succinate; Trolox and corresponding amide and thiocarboxamide analog; Ascorbic acid and salt thereof, arabo-ascorbic acid, (2 or 3 or 6)-neighbour-alkyl ascorbic acid, acid ascorbyl ester (for example 6-neighbour-lauroyl, myristoyl, palmityl, oleoyl or inferior oleoyl-L-ascorbic acid etc.).Preferably the chemical compound of oxidation also is useful, for example sodium sulfite, inclined to one side-sodium sulfite, thiourea; Chelating is such as EDTA, GDTA, deferoxamine mesylate (desferral); Various endogenous systems of defense, for example transferrins, lactoferrin, ferritin, cearuloplasmin, haptoglobin (haptoglobion), blood clotting galactenzyme, albumin, glucose, pantothenylol-10; Enzymatic antioxidant, for example superoxide dismutase and have similar active metal complex comprises catalase, glutathion peroxidase and less complex molecule, for example beta-carotene, bilirubin, uric acid; Flavone compound (for example flavone, flavonol, flavanone, flavane aldehyde (flavanonals), card solanone (chacones), cyanine glycoside), N-acetylcystein, mesna, glutathion, sulfur histidine derivative, triazole; Tannic acid, cinnamic acid, hydroxyl cinnamic acid and ester thereof (coumaric acid and ester thereof, caffeic acid and ester thereof, ferulic acid, (different-) chlorogenic acid, sinapic acid); Spice extract (for example, from Flos Caryophylli, Cortex Cinnamomi, Salvia farinacea, Herba Rosmarini Officinalis, Arillus Myristicae, oregano, allspice, Semen Myristicae); Carnosic acid, carnosol, carsolic acid; Rosmarinic acid, Herba Rosmarini Officinalis diphenol, gentisic acid, ferulic acid; Oatmeal extract, for example Avena threonyl amine 1 and 2; Thioether, disulfide, sulfoxide, curing tetraalkyl thiuram; Phytic acid, steroid derivatives (for example U74006F); Tryptophan metabolism thing (for example 3-hydroxykynurenine, 3-hydroxyl ortho-aminobenzoic acid) and organic chalcogenide (organochalcogenide).

Use " thickening agent " to increase the viscosity of pharmaceutical preparation, and can be selected from: pharmaceutically acceptable hydrophilic polymer, such as the cellulose derivative of part etherificate, comprise carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose or methylcellulose; Synthetic hydrophilic polymer comprises polyacrylate fully, polymethacrylate, poly-(ethoxy) methacrylate, poly-(hydroxypropyl) methacrylate, poly-(hydroxypropyl methyl) methacrylate, polyacrylonitrile, methallyl sulfonate, polyethylene kind, polyoxyethylene, polyethylene glycols, Polyethylene Glycol-lactide, Polyethylene Glycol-diacrylate, polyvinylpyrrolidone, polyvinyl alcohol, poly-(propyl methyl amide), poly-(fumaric acid propylene glycol-copolymerization-ethylene glycol), the poloxamer class, poly-asparagine, (hydrazine is crosslinked) hyaluronic acid, organosilicon; Natural gum comprises alginate, carrageenin, guar gum, gelatin, Tragacanth, (amidated) pectin, xanthan gum, chitosan, collagen, agarose; Their mixture and further on derivant or copolymer and/or the other medicines or biologically at least acceptable polymer.

Antifungal preparation of the present invention also can comprise polar liquid medium.Local antifungal preparation of the present invention can be used in aqueous medium.Antifungal preparation of the present invention can be the form of solution, suspensoid, Emulsion, ointment, lotion, ointment, gel, spray, film forming solution or lacquer agent.

In one embodiment, the present invention relates to the application that antifungal, phospholipid and nonionic surfactant are used to prepare the pharmaceutical composition for the treatment of tinea unguium particularly.In this context, the present invention relates to be used for the treatment of the preparation that comprises antifungal or the pharmaceutical composition of tinea unguium, wherein said preparation or pharmaceutical composition are mixed with local delivery.

Table 7 has been listed the preferred excipient of said preparation.

4.4. vesicle formation

Although be not limited to any mechanism of action or any theory, preparation of the present invention can form the vesicle or the ESA of the adaptability, deformability or the penetrance that are characterised in that them.

Term vesicle or aggregation " adaptability " (it determines " surface curvature that can tolerate ") are defined as the ability that specific vesicle or aggregation easily change its character (such as shape, ratio of elongation and S/V).The feature of vesicle of the present invention can be that they regulate the shape of aggregation and the ability of character according to passed the anisotropic stress that causes by the hole.Enough adaptability hints, vesicle or aggregation can stand different unidirectional forces or stress, and such as the power that is caused by pressure, and extensively not broken, it has defined " stable " aggregation.If aggregation passes the barrier that satisfies this condition, then term " adaptability " and (shape) " deformability "+" permeability " are equivalent basically.In the context of the present invention, " barrier " is to have (as in for example EP 0 475 160 and WO 98/17255) main body that connects narrowed aperture, and the described ESA of the radius ratio of such narrowed aperture passes the radius little at least 25% of the ESA (regarding spheroid as) before these holes.

The term of related use with the hole " narrow " hint, pore radius is significantly less than the radius of the entity of testing about its ability of passing the hole, and is little usually by at least 25%.For narrower hole, this necessary difference usually should be bigger.Therefore, for＞the 150nm diameter, it is very suitable using 25% limit, and for littler system, for example＜and the 50nm diameter,＞100% difference requirements is more suitable for.For the diameter about 20nm, often need at least 200% aggregation diameter difference.

The term of related use " semipermeable " hint with barrier, solution can pass strides the barrier opening, and the suspensoid of immalleable aggregation (even as big as the definition in " narrow " hole above being suitable for) then can not.By at any common phosphatidylcholine or any biological phosphatidylcholine/cholesterol 1/1mol/mol mixture or the sizable oil droplet conventional lipid vesicle (lipid body) (they all have specified relative diameter) made of gel layer in mutually, be 3 examples of this immalleable aggregation.

Term " stable " is meant, the aggregation of test fail spontaneously or under the relevant mechanical stress of transportation (during for example passing semipermeable barrier) unacceptably (this most commonly only represents pharmaceutically acceptable degree) change their diameter.The 20-40% variation is considered acceptable usually; Reducing by half or doubling of aggregation diameter is the border, and the bigger variation of diameter is normally unacceptable.Perhaps and easily, use and under pressure, pass the aggregation diameter variation that causes and come evaluating system stability by the hole; Then with identical standard application in " narrow " hole, do necessary correction in detail.In order to obtain the right value of aggregation vary in diameter, the correction of flux/vortex effect may be necessary.These rules are described in greater detail in applicant's the publication: people such as Cevc, and Biochim.Biophys.Acta 2002; 1564:21-30.

The non-destructive of the narrowed aperture in super deformed, the blended fat aggregation semi-permeable barrier is passed, thereby is the adaptive diagnostic characteristic of high aggregation.If pore radius is 1/2 of an average aggregate radius, shape and S/V that aggregation must 100% ground changes it at least just can pass barrier and not broken.Easy and the reversible variation of aggregate shapes must hint high aggregation deformability and need big S/V to adapt to.The variation of S/V is hinting in itself: a) high coefficient of bulk compressibility, for example under the situation of fine and close microdroplet, described fine and close microdroplet contain except suspensoid and with the immiscible material of suspensoid; B) high aggregation membrane permeability, for example under the situation of such vesicle, described vesicle is free replacement fluids between interior and outer vesicle volume.

4.5 application process

Another aspect of the present invention provides the method for using the pharmaceutical composition that comprises antifungal, lipid and surfactant.Generally speaking, pharmaceutical composition is applied to nail tissue.For example, in certain embodiments, it is applied to nail tissue partly.

Term used herein " nail tissue " is used for describing any tissue as the component of " fingernail unit ".The fingernail unit comprises substrate, nail plate, nail matrix, horny layer, lunula of nail and hyponychium.Substrate is wherein cell proliferation before the nail plate is entered in fusion and cornified place.This tissue is from the about 5mm of first pleat near-end, and covering is called the whole zone of " lunula of nail " or " first quarter moon ".Substrate is avoided infecting by horny layer (folding the improved cuticular of nail plate near-end) protection.

In one embodiment, topical formulations is applied to human experimenter's nail tissue and/or surrounding skin, produces every gram nail tissue antifungal mean concentration of 1.5mg/g, 2.0mg/g, 2.1mg/g, 2.2mg/g, 2.3mg/g, 2.4mg/g, 2.5mg/g, 2.6mg/g, 2.7mg/g, 2.8mg/g, 2.9mg/g and 3.0mg/g approximately at least.In another embodiment, topical formulations is applied to human experimenter's nail tissue, produces every gram nail tissue about 0.1 to about 15mg/g, about 0.2 to about 12.5mg/g, about 0.5 to about 10.0mg/g, about 1.0 antifungal mean concentrations to about 7.5mg/g or about 2.0 to about 5.0mg/g.1,2 or 3 weeks can be measured mean concentration after stopping to use topical formulations.The present invention also provides the method for the fungal infection of the nail tissue for the treatment of the human experimenter, it comprises infected nail tissue and/or the surrounding skin that topical formulations is applied to the human experimenter, produces every gram nail tissue about 0.1 to about 15mg/g, about 0.2 to about 12.5mg/g, about 0.5 to about 10.0mg/g, about 1.0 antifungal mean concentrations to about 7.5mg/g or about 2.0 to about 5.0mg/g.1,2 or 3 weeks can be measured mean concentration after stopping the drug administration compositions.

In some embodiment of described method, local antifungal preparation of the present invention use also the antifungal average serum concentration that in the human experimenter, produces less than 10.0ng/ml, 5.0ng/ml, 4.0ng/ml, 3.0ng/ml, 2.0ng/ml, 1.0ng/ml, 0.5ng/ml or 0.2ng/ml.

In some embodiment of described method, topical formulations comprises about 1.0 to about 5.0mg antifungal.In a specific embodiments of described method, described pharmaceutical composition comprises the 3.0mg antifungal.For example administration every day 2 times of topical formulations.In certain embodiments, described compositions also can administration in per 2 days 1 time, every day 1 time, every day 3 times or every day 4 times.In certain embodiments, at least 3 weeks of topical formulations administration.In other embodiments, topical formulations administration 3-48 week, 3-36 week or 3-24 week, 3-12 week or 3-6 week.

In a specific embodiments of described method, 12 weeks of topical formulations administration, infect with the treatment nail fungi, assess then, to determine whether that reaching mycology cures.Cure if reached mycology, stop further administration topical formulations.Do not cure if reach mycology as yet, then use the topical formulations time in other 12 weeks again, carry out the assessment second time subsequently, to determine whether this scheme has reached healing.Can repeat this circulation, reach mycology up to this scheme and cure.In certain embodiments, described preparation is fit to cause the mycology cure rate greater than 90%.

In another embodiment, the topical formulations that will comprise antifungal, lipid and surfactant is administered to nail tissue and/or surrounding skin, every day 2 times, continues at least 1,2 or 3 weeks.The present invention also provides the method for the fungal infection of the nail tissue for the treatment of the human experimenter, it comprises infected nail tissue and the surrounding skin that topical formulations is applied to the human experimenter, every day 2 times, continued at least 1,2 or 3 weeks, wherein said topical formulations comprises antifungal, lipid and surfactant.

In some embodiment of described method, described topical formulations also can administration in per 2 days 1 time, every day 1 time, every day 3 times or every day 4 times.In specific embodiments, topical formulations administration 3-48 week, 3-36 week or 3-24 week, 3-12 week or 3-6 week.

In some embodiment of described method, topical formulations comprises about 1.0 to about 5.0mg antifungal.For example, topical formulations can comprise about 3.0mg antifungal.

In a specific embodiments, fungal infection to be treated comprises tinea unguium.

In some embodiment of methods described herein, the topical formulations administration surpasses the time in 12 weeks.For example, in certain embodiments, at least 24 weeks of topical formulations administration, at least 36 week or at least 48 weeks.

In some embodiment of described method, adopt the circulation treatment scheme.Such scheme adopts such treatment circulation, and it comprises uses topical formulations a period of time, succeeded by time period of administered formulation not, and where necessary, repeats this order, promptly circulates.Treatment circulation can comprise that for example, the time in 12 weeks of continuous administration topical formulations is short, for example, uses 2 administrations every day, succeeded by period of administered formulation not, is once more another time period in other 12 weeks of continuous administration preparation then.

Some embodiment of described method comprises such therapeutic scheme, wherein uses topical formulations and treats nail fungi infection a period of time, assesses the experimenter subsequently, to determine whether administration has reached mycology and cured in the experimenter.Cure if reached mycology, stop further administration topical formulations.Do not cure if reach mycology as yet, then in second medicine-feeding period, use topical formulations again, carry out the assessment second time subsequently, to determine whether this scheme has reached healing.Can repeat this circulation, reach mycology up to this scheme and cure.

In certain embodiments, the present invention relates to use medication as herein described to treat specific group of patients.In certain embodiments, use medication as herein described, can treat the patient colony that infected by nail fungi.In a specific embodiment, use method as herein described, can treat and continued again the patient colony that infects.For example, first administration time section (for example, preceding 12 time-of-week sections), topical formulations can be administered to such colony, be second follow-up administration time section (for example, other 12 time-of-week sections) then, with the infection again of prevention nail tissue.

In other embodiments, can prophylactically use medication as herein described, so that prevention suffers the infection again of the nail tissue of the patient colony that nail fungi infects for a long time.

4.5 test kit

The present invention comprises pharmaceutical pack or the test kit that is used for the treatment of or prevents human experimenter's fungal infection in addition, and it comprises one or more containers, and described container is equipped with antifungal preparation of the present invention.The invention provides the test kit that can be used for said method.

In one embodiment, test kit comprises one or more containers, and described container is equipped with antifungal preparation of the present invention.Test kit can comprise in addition about using the description of antifungal preparation treatment of the present invention or prevention skin and/or nail infection and side effect and dosage information.These containers are randomly with the points for attention of the form of government organs' regulation of production, use or the sale of administrative man's medication.

5. embodiment

5.1 embodiment 1: antifungal preparation

According to following rules, can prepare and be used for the local antifungal preparation that uses:

1. organic facies production, it contains all lipophilic excipient

Following production organic facies: weighing lipid, surfactant, antifungal hydrochloride and extra arbitrarily lipophilic excipient are mixed into these components isotropic phase of optically-active subsequently in suitable containers, it presents settled solution.In mixed process, the heating organic facies, but temperature must be no more than 45 ℃.

2. water production

Following production water: weighing is non--and lipophilic component and water (as solvent) in suitable containers, is mixed into settled solution with these components subsequently.In mixed process, elevate the temperature to 40 ℃.

3. produce mutually by two of combinations and concentrate intermediate

In suitable containers, under agitation, merge isotropic organic facies and clarifying water.Before mixing and in the process, the temperature of two phases must remain on 35 ℃ to 45 ℃.At 40 ℃, the intermediate that mechanically homogenizes and obtain.Before beginning to homogenize, the pressure of producing in the container is reduced to-0.08MPa.Usually after homogenizing 10 minutes, reach the average carrier size of hope.

In the process of producing spissated intermediate, must control 3 procedure parameters carefully: temperature, homogenizer circulation rate and total processing time.

4. by merging spissated intermediate and dilution buffer liquid, produce final raw material product (bulkproduct).

Dilute the final concentration of spissated intermediate with dilution buffer liquid to expection.Stir the mixture to homogeneity carefully in mixer at 20 ℃.

Table 8 has been described the amount of surfactant, lipid and one or more antifungal (for example, terbinafine) in preferred antifungal preparation of the present invention.In the mode of the percent of total in preparation, the amount of one or more antifungal, lipid, lipid and the surfactant that merge is described.Tested in the body of one of following Terbinafine formulation and renderd a service.

Embodiment preparation 1

Preparation 1 comprise antifungal (10mg/g), sphingomyelins (brain) (47.944mg/g) as lipid, Tween 80 (42.056mg/g) as surfactant, lactate buffer (pH 4), benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.0500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 2

Preparation 2 comprise antifungal (15mg/g), sphingomyelins (brain) (53.750mg/g) as lipid, Tween 80 (31.250mg/g) as surfactant, lactate (pH 4) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (15.000mg/g).

Embodiment preparation 3

Preparation 3 comprise antifungal (30mg/g), sphingomyelins (brain) (90.561mg/g) as lipid, Tween 80 (79.439mg/g) as surfactant, lactate (pH 4) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 4

Preparation 4 comprise antifungal (10mg/g), sphingomyelins (brain) (47.944mg/g) as lipid, Tween 80 (42.056mg/g) as surfactant, lactate (pH 5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 5

Preparation 5 comprise antifungal (5mg/g), sphingomyelins lauroyl (sphingomyelinlauroyl) (50.607mg/g) as lipid, Brij 98 (44.393mg/g) as surfactant, acetate (pH 5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, EDTA (3.000mg/g) as chelating agen and ethanol (10.000mg/g).

Embodiment preparation 6

Preparation 6 comprise antifungal (30mg/g), sphingomyelins lauroyl (90.561mg/g) as lipid, Brij 98 (79.439mg/g) as surfactant, acetate (pH 5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 7

Preparation 7 comprise antifungal (7.5mg/g), sphingomyelins lauroyl (49.276mg/g) as lipid, Brij 98 (79.439mg/g) as surfactant, acetate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 8

Preparation 8 comprise antifungal (15mg/g), phosphatldylcholine and phosphatidyl glycerol (53.750mg/g) as lipid, Brij 98 (31.250mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, HTHQ (0.200mg/g) as antioxidant, glycerol (30.000mg/g) and EDTA (3.000mg/g) as chelating agen.

Embodiment preparation 9

Preparation 9 comprise antifungal (30mg/g), phosphatldylcholine and phosphatidyl glycerol (90.561mg/g) as lipid, Brij 98 (79.439mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, HTHQ (0.200mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 10

Preparation 10 comprise antifungal (10mg/g), phosphatldylcholine and phosphatidyl glycerol (41.351mg/g) as lipid, Brij 98 (48.649mg/g) as surfactant, phosphate (pH4) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, HTHQ (0.200mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 11

Preparation 11 comprise antifungal (15mg/g), phosphatldylcholine and phosphatidyl glycerol (47.882mg/g) as lipid, Brij 98 (37.118mg/g) as surfactant, phosphate (pH 4) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, HTHQ (0.200mg/g) as antioxidant, glycerol, EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 12

Preparation 12 comprise antifungal (30mg/g), phosphatldylcholine and phosphatidyl glycerol (95.764mg/g) as lipid, Brij 98 (74.236mg/g) as surfactant, phosphate (pH 4) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, HTHQ (0.200mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 13

Preparation 13 comprise antifungal (10mg/g), phosphatldylcholine and phosphatidylinositols (66.676mg/g) as lipid, span 20 (24.324mg/g) as surfactant, acetate (pH 5) buffer, benzyl alcohol (5.250mg/g), HTHQ (0.200mg/g) as antioxidant, EDTA (3.000mg/g) as chelating agen and ethanol (25.000mg/g).

Embodiment preparation 14

Preparation 14 comprise antifungal (15mg/g), phosphatldylcholine and phosphatidylinositols (62.027mg/g) as lipid, span 20 (22.973mg/g) as surfactant, acetate (pH 5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, HTHQ (0.200mg/g) as antioxidant, EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 15

Preparation 15 comprise antifungal (30mg/g), phosphatldylcholine and phosphatidylinositols (124.054mg/g) as lipid, span 20 (45.946mg/g) as surfactant, acetate (pH 5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, HTHQ (0.200mg/g) as antioxidant, glycerol (30.000mg/g) and EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 16

Preparation 16 comprise antifungal (5mg/g), phosphatldylcholine and phosphatidylinositols (62.687mg/g) as lipid, span 20 (32.313mg/g) as surfactant, acetate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, HTHQ (0.200mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen.

Embodiment preparation 17

Preparation 17 comprise antifungal (15mg/g), phosphatldylcholine and phosphatidic acid (41.853mg/g) as lipid, Tween 80 (43.147mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

Embodiment preparation 18

Preparation 18 comprise antifungal (30mg/g), phosphatldylcholine and phosphatidic acid (95.764mg/g) as lipid, Tween 80 (74.236mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) as antioxidant, EDTA (3.000mg/g) and ethanol (30.000mg/g).

Embodiment preparation 19

Preparation 19 comprise antifungal (15mg/g), phosphatldylcholine and phosphatidic acid (47.882mg/g) as lipid, Tween 80 (37.118mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) as antioxidant and EDTA (3.000mg/g).

Embodiment preparation 20

Preparation 20 comprise antifungal (10mg/g), phosphatldylcholine and phosphatidic acid (45.000mg/g) as lipid, Tween 80 (45.000mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) as antioxidant and EDTA (3.000mg/g).

Embodiment preparation 21

Preparation 21 comprise antifungal (10mg/g), phosphatldylcholine (31.935mg/g) as lipid, breast floating (58.065mg/g) as surfactant, lactate (pH 5) buffer, thimerosal (5.250mg/g) as antimicrobial, BHA (0.200mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (15.000mg/g).

Embodiment preparation 22

Preparation 22 comprise antifungal (15mg/g), phosphatldylcholine (42.500mg/g) as lipid, breast floating (42.500mg/g) as surfactant, lactate (pH 6.5) buffer, thimerosal (5.250mg/g) as antimicrobial, BHA (0.200mg/g) as antioxidant, glycerol (30.000mg/g) and EDTA (3.000mg/g) as chelating agen.

Embodiment preparation 23

Preparation 23 comprise antifungal (10mg/g), phosphatldylcholine (38.276mg/g) as lipid, breast floating (51.724mg/g) as surfactant, lactate (pH 4) buffer, thimerosal (5.250mg/g) as antimicrobial, BHA (0.200mg/g) as antioxidant, EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 24

Preparation 24 comprise antifungal (15mg/g), phosphatldylcholine (42.500mg/g) as lipid, breast floating (42.500mg/g) as surfactant, lactate (pH 4) buffer, thimerosal (5.250mg/g) as antimicrobial, BHA (0.200mg/g) as antioxidant, EDTA (3.000mg/g) as chelating agen and ethanol (15.000mg/g).

Embodiment preparation 25

Preparation 25 comprise antifungal (30mg/g), phosphatldylcholine (85.000mg/g) as lipid, breast floating (85.000mg/g) as surfactant, lactate (pH 4) buffer, thimerosal (5.250mg/g) as antimicrobial, BHA (0.200mg/g) as antioxidant, EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 26

Preparation 26 comprise antifungal (10mg/g), phosphatldylcholine (38.276mg/g) as lipid, breast floating (51.276mg/g) as surfactant, lactate (pH 5) buffer, thimerosal (5.250mg/g) as antimicrobial, BHA (0.200mg/g) as antioxidant and EDTA (3.000mg/g) as chelating agen.

Embodiment preparation 27

Preparation 27 comprise antifungal (15mg/g), phosphatldylcholine (36.429mg/g) as lipid, breast floating (48.571mg/g) as surfactant, lactate (pH 5) buffer, thimerosal (5.250mg/g) as antimicrobial, BHA (0.200mg/g) as antioxidant, EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 28

Preparation 28 comprise antifungal (30mg/g), phosphatldylcholine (72.299mg/g) as lipid, breast floating (97.701mg/g) as surfactant, lactate (pH 5) buffer, thimerosal (5.250mg/g) as antimicrobial, BHA (0.200mg/g) as antioxidant, EDTA (3.000mg/g) as chelating agen and ethanol (15.000mg/g).

Embodiment preparation 29

Preparation 29 comprise antifungal (7.5mg/g), PHOSPHATIDYL ETHANOLAMINE (46.250mg/g) as lipid, Tween 80 (46.250mg/g) as surfactant, phosphate (pH 6.5) buffer, thimerosal (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, EDTA (3.000mg/g) as chelating agen and ethanol (20.000mg/g).

Embodiment preparation 30

Preparation 30 comprise antifungal (15mg/g), PHOSPHATIDYL ETHANOLAMINE (38.804mg/g) as lipid, Tween 80 (46.196mg/g) as surfactant, phosphate (pH 6.5) buffer, thimerosal (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (15.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 31

Preparation 31 comprise antifungal (30mg/g), PHOSPHATIDYL ETHANOLAMINE (36.667mg/g) as lipid, Tween 80 (33.333mg/g) as surfactant, phosphate (pH 6.5) buffer, thimerosal (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 32

Preparation 32 comprise antifungal (10mg/g), phosphatidyl glycerol (23.333mg/g) as lipid, Brij 98 (66.667mg/g) as surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) as antioxidant and EDTA (3.000mg/g) as chelating agen.

Embodiment preparation 33

Preparation 33 comprise antifungal (12.5mg/g), phosphatidyl glycerol (45.833mg/g) as lipid, Brij 98 (41.667mg/g) as surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) as antioxidant, glycerol (30.000mg/g) and EDTA (3.000mg/g) as chelating agen.

Embodiment preparation 34

Preparation 34 comprise antifungal (30mg/g), phosphatidyl glycerol (31.957mg/g) as lipid, Brij 98 (38.043mg/g) as surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) as antioxidant, EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 35

Preparation 35 comprise antifungal (10mg/g), phosphatidyl glycerol (47.143mg/g) as lipid, Brij 98 (42.857mg/g) as surfactant, acetate (pH 5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (25.000mg/g).

Embodiment preparation 36

Preparation 36 comprise antifungal (15mg/g), phosphatidyl glycerol (96.905mg/g) as lipid, Brij 98 (88.095mg/g) as surfactant, acetate (pH 5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (20.000mg/g).

Embodiment preparation 37

Preparation 37 comprise antifungal (30mg/g), phosphatidyl glycerol (31.957mg/g) as lipid, Brij 98 (38.043) as surfactant, acetate (pH 5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) as antioxidant, EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 38

Preparation 38 comprise antifungal (10mg/g), PHOSPHATIDYL ETHANOLAMINE (35.455mg/g) as lipid, breast floating (54.545mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g) and EDTA (3.000mg/g) as chelating agen.

Embodiment preparation 39

Preparation 39 comprise antifungal (15mg/g), PHOSPHATIDYL ETHANOLAMINE (84.457mg/g) as lipid, breast floating (100.543mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 40

Preparation 40 comprise antifungal (30mg/g), PHOSPHATIDYL ETHANOLAMINE (89.048mg/g) as lipid, breast floating (80.952mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 41

Preparation 41 comprise antifungal (10mg/g), phosphatidyl glycerol (41.087mg/g) as lipid, Tween 80 (48.913mg/g) as surfactant, propionate (pH 4) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 42

Preparation 42 comprise antifungal (15mg/g), phosphatidyl glycerol (45.280mg/g) as lipid, Tween 80 (39.720mg/g) as surfactant, propionate (pH 4) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) and EDTA (3.000mg/g) as chelating agen.

Embodiment preparation 43

Preparation 43 comprise antifungal (30mg/g), phosphatidyl glycerol (107.500mg/g) as lipid, Tween 80 (62.500mg/g) as surfactant, propionate (pH 4) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 44

Preparation 44 comprise antifungal (5mg/g), phosphatidyl glycerol (77.243mg/g) as lipid, Tween 80 (67.757mg/g) as surfactant, propionate (pH 4) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 45

Preparation 45 comprise antifungal (15mg/g), phosphatidyl glycerol (45.280mg/g) as lipid, Tween 80 (39.720mg/g) as surfactant, propionate (pH 5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 46

Preparation 46 comprise antifungal (30mg/g), phosphatidyl glycerol (90.561mg/g) as lipid, Tween 80 (79.439mg/g) as surfactant, propionate (pH 5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 47

Preparation 47 comprise antifungal (10mg/g), phosphatidyl glycerol (47.944mg/g) as lipid, Tween 80 (42.056mg/g) as surfactant, propionate (pH 5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, EDTA (3.000mg/g) as chelating agen and ethanol (10.000mg/g).

Embodiment preparation 48

Preparation 48 comprise antifungal (5mg/g), Phosphatidylserine (50.607mg/g) as lipid, Brij 98 (44.393mg/g) as surfactant, phosphate (pH 5.5) buffer, thimerosal (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g) and EDTA (3.000mg/g) as chelating agen.

Embodiment preparation 49

Preparation 49 comprise antifungal (30mg/g), Phosphatidylserine (107.500mg/g) as lipid, Brij 98 (62.500mg/g) as surfactant, phosphate (pH 5.5) buffer, thimerosal (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g) and EDTA (3.000mg/g) as chelating agen.

Embodiment preparation 50

Preparation 50 comprise antifungal (10mg/g), Phosphatidylserine (47.944mg/g) as lipid, Brij 98 (42.056mg/g) as surfactant, phosphate (pH 5.5) buffer, thimerosal (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 51

Preparation 51 comprise antifungal (15mg/g), phosphatidyl glycerol (46.364mg/g) as lipid, Brij 98 (38.636mg/g) as surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (25.000mg/g).

Embodiment preparation 52

Preparation 52 comprise antifungal (15mg/g), phosphatidyl glycerol (46.364mg/g) as lipid, Brij 98 (38.636mg/g) as surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) as antioxidant, EDTA (3.000mg/g) as chelating agen and ethanol (20.000mg/g).

Embodiment preparation 53

Preparation 53 comprise antifungal (10mg/g), phosphatidyl glycerol (46.098mg/g) as lipid, Brij 98 (43.902mg/g) as surfactant, acetate (pH 5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) as antioxidant, glycerol (15.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 54

Preparation 54 comprise antifungal (15mg/g), phosphatidyl glycerol (43.537mg/g) as lipid, Brij 98 (41.463mg/g) as surfactant, acetate (pH 5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) as antioxidant, glycerol (30.000mg/g) and EDTA (3.000mg/g) as chelating agen.

Embodiment preparation 55

Preparation 55 comprise antifungal (10mg/g), phosphatidyl glycerol (45.000mg/g) as lipid, Brij 98 (45.000mg/g) as surfactant, acetate (pH 5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) as antioxidant, EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 56

Preparation 56 comprise antifungal (10mg/g), phosphatidyl glycerol (59.492mg/g) as lipid, Brij 98 (30.508mg/g) as surfactant, acetate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 57

Preparation 57 comprise antifungal (15mg/g), phosphatidyl glycerol (39.054mg/g) as lipid, Brij 98 (45.946mg/g) as surfactant, acetate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) as antioxidant and EDTA (3.000mg/g) as chelating agen.

Embodiment preparation 58

Preparation 58 comprise antifungal (30mg/g), phosphatidyl glycerol (35.854mg/g) as lipid, Brij 98 (34.146mg/g) as surfactant, acetate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) as antioxidant, glycerol (30.000mg/g) and EDTA (3.000mg/g) as chelating agen.

Embodiment preparation 59

Preparation 59 comprise antifungal (10mg/g), phosphatldylcholine (50.000mg/g) as lipid, Tween 80 (40.000mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 60

Preparation 60 comprise antifungal (10mg/g), phosphatldylcholine (38.571mg/g) as lipid, Tween 80 (51.429mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

Embodiment preparation 61

Preparation 61 comprise antifungal (7.5mg/g), phosphatldylcholine (41.954mg/g) as phospholipid, Tween 80 (50.546mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

Embodiment preparation 62

Preparation 62 comprise antifungal (10mg/g), phosphatldylcholine (42.632mg/g) as lipid, Tween 80 (47.368mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 63

Preparation 63 comprise antifungal (10mg/g), phosphatldylcholine (46.098mg/g) as lipid, Tween 80 (43.902mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 64

Preparation 64 comprise antifungal (10mg/g), phosphatldylcholine (39.721mg/g) as lipid, Tween 80 (50.279mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 65

Preparation 65 comprise antifungal (5mg/g), phosphatldylcholine (44.198mg/g) as lipid, Tween 80 (50.802mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 66

Preparation 66 comprise antifungal (2.5mg/g), phosphatldylcholine (46.453mg/g) as lipid, Tween 80 (51.047mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 67

Preparation 67 comprise antifungal (5mg/g), phosphatldylcholine (51.221mg/g) as lipid, Tween 80 (43.779mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 68

Preparation 68 comprise antifungal (2.5mg/g), phosphatldylcholine (54.167mg/g) as lipid, Tween 80 (43.333mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 69

Preparation 69 comprise antifungal (10mg/g), phosphatldylcholine (66.440mg/g) as lipid, Brij 98 (23.560mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).Embodiment preparation 69 is an Emulsion.

Embodiment preparation 70

Preparation 70 comprise antifungal (10mg/g), phosphatldylcholine (66.440mg/g) as lipid, Brij 98 (23.560mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).Embodiment preparation 70 is suspensoids.

Embodiment preparation 71

Preparation 71 comprise antifungal (10mg/g), phosphatldylcholine (66.440mg/g) as lipid, Brij 98 (23.560mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 72

Preparation 72 comprise antifungal (10mg/g), phosphatldylcholine (40.000mg/g) as lipid, Tween 80 (50.000mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).Embodiment preparation 72 is an Emulsion.

Embodiment preparation 73

Preparation 73 comprise antifungal (10mg/g), phosphatldylcholine (40.000mg/g) as lipid, Tween 80 (50.000mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).Embodiment preparation 73 is suspensoids.

Embodiment preparation 74

Preparation 74 comprise antifungal (10mg/g), phosphatldylcholine (40.000mg/g) as lipid, Tween 80 (50.000mg/g) as surfactant, acetate (pH 5.5) buffer, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 75

Preparation 75 comprise antifungal (10mg/g), phosphatldylcholine (40.000mg/g) as lipid, Tween 80 (50.000mg/g) as surfactant, phosphate (pH 6.5) buffer, p-Hydroxybenzoate (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 76

Preparation 76 comprise antifungal (10mg/g), phosphatldylcholine (40.000mg/g) as lipid, Brij 98 (50.000mg/g) as surfactant, phosphate (pH 6.5) buffer, benzalkonium chloride (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 77

Preparation 77 comprise antifungal (10mg/g), phosphatldylcholine (40.000mg/g) as lipid, Tween 80 (50.000mg/g) as surfactant, phosphate (pH 6.5) buffer, p-Hydroxybenzoate (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 78

Preparation 78 comprise antifungal (10mg/g), phosphatldylcholine (66.440mg/g) as lipid, Brij 98 (23.560mg/g) as surfactant, phosphate (pH 6.5) buffer, benzalkonium chloride (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 79

Preparation 79 comprise antifungal (10mg/g), phosphatldylcholine (66.440mg/g) as lipid, Brij 98 (23.560mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 80

Preparation 80 comprise antifungal (10mg/g), phosphatldylcholine (40.000mg/g) as lipid, Tween 80 (50.000mg/g) as surfactant, acetate (pH 5.5) buffer, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 81

Preparation 81 comprise antifungal (10mg/g), phosphatldylcholine (40.000mg/g) as lipid, Tween 80 (50.000mg/g) as surfactant, acetate (pH 5.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 82

Preparation 82 comprise antifungal (10mg/g), phosphatldylcholine (44.444mg/g) as lipid, Tween 80 (55.556mg/g) as surfactant, acetate (pH 5.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 83

Preparation 83 comprise antifungal (10mg/g), phosphatldylcholine (66.440mg/g) as lipid, Tween 80 (23.560mg/g) as surfactant, acetate (pH 5.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 84

Preparation 84 comprise antifungal (10mg/g), phosphatldylcholine (54.000mg/g) as lipid, Tween 80 (36.000mg/g) as surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHA (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 85

Preparation 85 comprise antifungal (10mg/g), phosphatldylcholine (50.000mg/g) as lipid, Tween 80 (40.000mg/g) as surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHA (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 86

Preparation 86 comprise antifungal (12.5mg/g), phosphatldylcholine (48.611mg/g) as lipid, Tween 80 (38.889mg/g) as surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHA (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 87

Preparation 87 comprise antifungal (15mg/g), phosphatldylcholine (46.575mg/g) as lipid, Tween 80 (38.425mg/g) as surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHA (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).Embodiment preparation 87 is an Emulsion.

Embodiment preparation 88

Preparation 88 comprise antifungal (15mg/g), phosphatldylcholine (46.575mg/g) as lipid, Tween 80 (38.425mg/g) as surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHA (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).Embodiment preparation 88 is suspensoids.

Embodiment preparation 89

Preparation 89 comprise antifungal (15mg/g), phosphatldylcholine (46.575mg/g) as lipid, Tween 80 (38.425mg/g) as surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 90

Preparation 90 comprise antifungal (10mg/g), phosphatldylcholine (50.000mg/g) as lipid, Tween 80 (40.000mg/g) as surfactant, acetate (pH 4.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 91

Preparation 91 comprise antifungal (30mg/g), phosphatldylcholine (94.444mg/g) as lipid, Tween 80 (75.556mg/g) as surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 92

Preparation 92 comprise antifungal (15mg/g), phosphatldylcholine (46.712mg/g) as lipid, Tween 80 (38.288mg/g) as surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 93

Preparation 93 comprise antifungal (12mg/g), phosphatldylcholine (48.889mg/g) as lipid, Tween 80 (39.111mg/g) as surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 94

Preparation 94 comprise antifungal (10mg/g), phosphatldylcholine (39.721mg/g) as lipid, Tween 80 (50.279mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.25mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 95

Preparation 95 comprise antifungal (10mg/g), phosphatldylcholine (90.000mg/g) as lipid, phosphate buffer (pH 6.5), benzyl alcohol as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 96

Preparation 96 comprise antifungal (15mg/g), phosphatldylcholine (46.575mg/g) as lipid, Tween 80 (38.425mg/g) as surfactant, phosphate (pH 4) buffer, BHT (0.500mg/g) and sodium pyrosulfite (0.200mg/g) as antioxidant and EDTA (3.000mg/g) as chelating agen.Embodiment preparation 96 is an Emulsion.

Embodiment preparation 97

Preparation 97 comprise antifungal (15mg/g), phosphatldylcholine (46.575mg/g) as lipid, Tween 80 (38.425mg/g) as surfactant, phosphate (pH 4) buffer, BHT (0.500mg/g) and sodium pyrosulfite (0.200mg/g) as antioxidant and EDTA (3.000mg/g).Embodiment preparation 97 is suspensoids.

Embodiment preparation 98

Preparation 98 comprise antifungal (15mg/g), phosphatldylcholine (54.643mg/g) as lipid, Tween 80 (30.357mg/g) as surfactant, phosphate (pH 4) buffer, BHA (0.500mg/g) and sodium pyrosulfite (0.200mg/g) as antioxidant and EDTA (3.000mg/g) as chelating agen.

Embodiment preparation 99

Preparation 99 comprise antifungal (10mg/g), phosphatldylcholine (39.72mg/g) as lipid, Tween 80 (50.279mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.25mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g) as softening agent, EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 100

Preparation 100 comprise antifungal (10mg/g), phosphatldylcholine (90.00mg/g) as lipid, phosphate (pH 6.5) buffer, benzyl alcohol as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) as antioxidant, glycerol (30.000mg/g) as softening agent, EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

Embodiment preparation 101

Preparation 101 comprise antifungal (15mg/g), phosphatldylcholine (46.57mg/g) as lipid, Tween 80 (38.425mg/g) as surfactant, phosphate (pH 4) buffer, BHT (0.500mg/g) and sodium pyrosulfite (0.200mg/g) as antioxidant and EDTA (3.000mg/g) as chelating agen.Preparation 101 is formulated as Emulsion.

Embodiment preparation 102

Preparation 102 comprise antifungal (15mg/g), phosphatldylcholine (46.57mg/g) as lipid, Tween 80 (38.425mg/g) as surfactant, phosphate (pH 4) buffer, BHT (0.500mg/g) and sodium pyrosulfite (0.200mg/g) as antioxidant and EDTA (3.000mg/g) as chelating agen.Preparation 102 is suspensoids.

Embodiment preparation 103

Preparation 103 comprise antifungal (15mg/g), phosphatldylcholine (54.64mg/g) as lipid, Tween 80 (30.357mg/g) as surfactant, phosphate (pH 4) buffer, BHA (0.500mg/g) and sodium pyrosulfite (0.200mg/g) as antioxidant, EDTA (3.000mg/g) as chelating agen.

Embodiment preparation 104

Preparation 104 comprise antifungal (6.1mg/g), phosphatldylcholine (46.58mg/g) as lipid, Tween 80 (38.43mg/g) as surfactant, benzyl alcohol (5.25mg/g) as antimicrobial, phosphate (pH 6.5) buffer, EDTA (3.000mg/g) as chelating agen, ethanol (30.000mg/g) and optional BHA (0.500mg/g) and sodium pyrosulfite (0.200mg/g) as antioxidant.

Embodiment preparation 105

Preparation 105 comprise antifungal (6.1mg/g), phosphatldylcholine (64.52mg/g) as lipid, Tween 80 (35.484mg/g) as surfactant, benzyl alcohol (5.25mg/g) as antimicrobial, phosphate (pH 6.5) buffer, EDTA (3.000mg/g) as chelating agen, ethanol (30.000mg/g) and optional BHA (0.500mg/g) and sodium pyrosulfite (0.200mg/g) as antioxidant.

Embodiment preparation 106

Preparation 106 comprise antifungal (6.1mg/g), phosphatldylcholine (66.44mg/g) as lipid, Tween 80 (23.56mg/g) as surfactant, benzyl alcohol (5.25mg/g) as antimicrobial, phosphate (pH 6.5) buffer, EDTA (3.000mg/g) as chelating agen, ethanol (30.000mg/g) and optional BHA (0.500mg/g) and sodium pyrosulfite (0.200mg/g) as antioxidant.

Embodiment preparation 107

Preparation 107 comprise antifungal (10mg/g), phosphatldylcholine (46.58mg/g) as lipid, Tween 80 (38.43mg/g) as surfactant, benzyl alcohol (5.25mg/g) as antimicrobial, phosphate (pH 6.5) buffer, EDTA (3.000mg/g) as chelating agen, ethanol (30.000mg/g) and optional BHA (0.500mg/g) and sodium pyrosulfite (0.200mg/g) as antioxidant.

Embodiment preparation 108

Preparation 105 comprise antifungal (10mg/g), phosphatldylcholine (64.52mg/g) as lipid, Tween 80 (35.484mg/g) as surfactant, benzyl alcohol (5.25mg/g) as antimicrobial, phosphate (pH 6.5) buffer, EDTA (3.000mg/g) as chelating agen, ethanol (30.000mg/g) and optional BHA (0.500mg/g) and sodium pyrosulfite (0.200mg/g) as antioxidant.

Embodiment preparation 109

Preparation 109 comprise antifungal (10mg/g), phosphatldylcholine (66.44mg/g) as lipid, Tween 80 (23.56mg/g) as surfactant, benzyl alcohol (5.25mg/g) as antimicrobial, phosphate (pH 6.5) buffer, EDTA (3.000mg/g) as chelating agen, ethanol (30.000mg/g) and optional BHA (0.500mg/g) and sodium pyrosulfite (0.200mg/g) as antioxidant.

Embodiment preparation 1 to 109 also can randomly comprise thickening agent, such as pectin, xanthan gum, HPMC gel, methylcellulose or carbopol.Embodiment preparation 1 to 103 can contain the salt of antifungal, antifungal or the derivant or the analog of terbinafine.

Use any antifungal disclosed herein, for example, the salt of terbinafine, terbinafine or the derivant of terbinafine or analog can prepare embodiment preparation 1 to 109.

Embodiment 2: research in the body of antifungal preparation effectiveness and pharmacokinetics

Effectiveness and pharmacokinetics that the local antifungal preparation that contains terbinafine is used for the treatment of tinea unguium have been studied.First purpose of this research is, is determined at Terbinafine formulation disclosed herein and treats mycology cure rate after 12 weeks.Terbinafine formulation is administered to 2 target areas of every experimenter, makes the 3.0mg terbinafine be delivered to each target area, every day 2 times (1 day 2 times), 12 weeks of medication.Continuous use is after 12 weeks, patient's therapy discontinued.Be defined as on each infected toenail the target area and 20cm on every side ²Area.In 2 weeks after the therapy discontinued (the 14th week of research),, cultivate and estimate succeeded by mycology with microscopy toenail sample.

5.1.1 estimate the measuring method of mycology cure rate

Cultivate definition mycology cure rate by the negative microscopy of potassium hydroxide (KOH) sample and the feminine gender of dermatophytes.

The mycology sample is taken from the patient.Central laboratory is used to handle the mycology sample.The patient can have extra screening and go to a doctor, if the KOH microscopy is male, and culture is the dermatophytes feminine gender, and they can be cultivated again so.If it is male that the result who repeats to cultivate is a dermatophytes, can register the patient, as long as he is in about 3 weeks are gone to a doctor in screening.

Specimen collection

In order to collect the fingernail cutting thing that is used to analyze, Mycotrans is collected bag be placed under the fingernail.Not causing under the excessively uncomfortable situation of patient, after the free edge of target toenail leans on as far as possible far, use nail clipper cutting target toenail.By scraping, the fragment under the fingernail of the crumbling below the fingernail edge of pruning of collecting.In sample, comprise fragment under Hyperkeratotic nail matrix and the fingernail.Also collect sample from part any variable color of big target toenail, dystrophic or brittle.

On the mycology sample, carry out the KOH wet mount microscopy of target toenail specimen and the mycology of dermatophytes and cultivate.The sample of clinical sample is coated on the selection agar (Merck of pathogenic fungus, Darmstadt, in Germany's (production number: 1.10415.0001)), so that separate and differentiate following species: trichophyton (T.rubrum), Trichophyton interdigitale (T.interdigitale), trichophyton (T.tonsurans) and other pathogenic dermatophytes and Candida albicans (C.albicans) and scopulariopsis brevicaulis (S.brevicaulis).Flat board 28 ℃ of incubation 1-4 weeks, is checked weekly, and with the suspicious bacterium colony of microscopy, and/or biochemical tested discriminating.

Finish 2 weeks of back in beginning Terbinafine formulation treatment back 14-week with in treatment, measure the mycology cure rate of 81 toenails.In 81 infected toenails, 73 show completely mycology and cure, and 8 do not have.The summary of data is as shown in table 9.

Table 9: at the mycology cure rate in 14-week

5.1.2 the mensuration of terbinafine serum and nail tissue concentration

Also studied the pharmacokinetics of local Terbinafine formulation.The purpose of this research is to measure the experimenter's who uses local Terbinafine formulation serum and the terbinafine concentration in the target toenail tissue.

The medication first time (0 hour) before and after using the local terbinafine of 6.0mg dosage 0.5,1,2,4,8 and 12 hour, take to be used for to measure the blood sample (2.7ml) of the terbinafine concentration of serum.Before using local Terbinafine formulation the every day second time, take after the administration for the first time 12 hours sample.

By LC-MSMS, the terbinafine of serum analysis sample.The interior mark that uses is a naftifine.By 50 μ L serum being joined in 50 μ L methanol and the 300 μ L internal standard solution (50 μ g/L naftifines 9: 1 acetonitrile/methanol solution in) the preparation sample.With solution left standstill 5 minutes, carry out centrifugal then.After centrifugal, 50 μ L supernatant are joined in the 450 μ L mobile phase solution.

In the 1st day and the 12nd week of research, measure serum-concentration.For all individualities,, confirm that blood serum sample contains stable state terbinafine and all the trough levels less than 1ng/ml in each time point experiment.

Also measured with the terbinafine concentration in the target toenail of local Terbinafine formulation treatment of the present invention.The fingernail cutting thing of collecting is carried out basic hydrolysis, use hexane extraction subsequently.All samples is carried out dilution in 1: 100.Measure terbinafine concentration by LC-MSMS then.At research the 14th week (this is to stop local Terbinafine formulation administration after 2 weeks), collect the nail samples that is used for this research and show the meansigma methods of 3.4mg/g nail tissue (STD 2.9).The median of the data of Shou Jiing is the 2.3mg/g nail tissue at this moment, and geometrical mean is the 2.4mg/g nail tissue.

5.1.3 clinical cure evaluation

Use standard method known in the art (referring to, for example, Tavakkol waits people TheAmerican Journal of Geriatric Pharmacotherapy.2006; 4:1-13), by the normal toenail growth of 2mm at least after 24 weeks, definition clinical cure.In order to assess clinical cure rate, measure from the unguish of the visible near side (ns) of fingernail, and whether nail growth normal and how many mm is normal to estimate nail growth.Under the situation of growing, think that fingernail is cured from the normal nail of near side (ns) 2mm (in the 24th week).

5.1.4 conclusion

These results' confirmations, when being applied to nail plate and surrounding skin partly, the tinea unguium that the antifungal preparation that comprises one or more antifungal (for example, terbinafine), lipid and surfactant disclosed herein can be treated the human experimenter effectively.Described antifungal preparation can provide the mycology cure rate greater than 90% effectively in suffering from the human experimenter of tinea unguium.Be proved invalid and can not successfully cure under the situation of nail infection at existing local antifungal preparation, described local antifungal preparation can provide effective treatment of tinea unguium.

Claims

1. treat the method for human experimenter's fungal infection, described method comprises the pharmaceutical preparation that comprises terbinafine, lipid and surfactant to experimenter's local application.

2. the process of claim 1 wherein that described fungal infection is a tinea unguium.

3. the process of claim 1 wherein that described pharmaceutical preparation is ointment, lotion, ointment, gel, solution, spray, lacquer agent or film forming solution.

4. the process of claim 1 wherein that terbinafine is a salt form.

5. the process of claim 1 wherein that terbinafine is a free alkali form.

6. the method for claim 4, wherein terbinafine is the HCl salt form.

7. the process of claim 1 wherein that described preparation contains the terbinafine of 0.5-10.0 weight %.

8. the method for claim 7, wherein said preparation contains the terbinafine of 1.5 weight %.

9. the process of claim 1 wherein that described lipid is phospholipid.

10. the method for claim 9, the ratio of wherein said phospholipid and surfactant is 1/1-5/1w/w.

11. the method for claim 9, wherein said preparation contains the phospholipid of 2.0-10.0 weight %.

12. the process of claim 1 wherein that described preparation contains the surfactant of 1.0-5.0 weight %.

13. the method for claim 9, wherein said phospholipid is phosphatidylcholine.

14. the process of claim 1 wherein that described surfactant is to be selected from following nonionic surfactant: polyoxyethylene sorbitan, poly-hydroxyl ethylene stearate or poly-hydroxyl ethylene lauryl ether.

15. the method for claim 14, wherein said surfactant are polyoxyethylene sorbitan monoleate (Tween 80s).

16. the method for claim 2, wherein said preparation are applied to experimenter's fingernail and/or surrounding skin.

17. the method for claim 2, the total daily dose that wherein is administered to infection site are 1.0 to 12.0mg.

18. the terbinafine that will effectively treat the amount of tinea unguium is delivered to the method for fingernail, it comprises that to experimenter's local application pharmaceutical preparation, described pharmaceutical preparation comprises terbinafine, lipid and the surfactant for the treatment of effective dose.

19. the method for claim 18, wherein said pharmaceutical preparation are ointment, lotion, ointment, gel, solution, spray, lacquer agent or film forming solution.

20. the method for claim 18, wherein terbinafine is a salt form.

21. the method for claim 18, wherein terbinafine is a free alkali form.

22. the method for claim 19, wherein terbinafine is the HCl salt form.

23. the method for claim 18, wherein said preparation contains the terbinafine of 0.5-5.0 weight %.

24. the method for claim 23, wherein said preparation contains the terbinafine of 1.5 weight %.

25. the method for claim 18, wherein said lipid is phospholipid.

26. the method for claim 25, wherein the ratio of phospholipid and surfactant is 1/1-5/1w/w.

27. the method for claim 25, wherein said preparation contains the phospholipid of 2-10 weight %.

28. the method for claim 25, wherein said phospholipid is phosphatidylcholine.

29. the method for claim 18, wherein said preparation contains the surfactant of 1-5 weight %.

30. the method for claim 18, wherein said surfactant are to be selected from following nonionic surfactant: polyoxyethylene sorbitan, poly-hydroxyl ethylene stearate or poly-hydroxyl ethylene lauryl ether.

31. the method for claim 30, wherein said surfactant are polyoxyethylene sorbitan monoleate (Tween 80s).

32. the method for claim 18, wherein said preparation are applied to experimenter's fingernail and/or surrounding skin.

33. the method for claim 18, the total daily dose that wherein is administered to infection site are 1.0 to 12.0mg.

34. the method for claim 1 or claim 18, wherein said preparation have the penetrating power to infection site of raising.

35. the preparation of terbinafine, it is included in terbinafine, lipid and surfactant in the aqueous solution, and wherein said preparation is fit to local delivery.

36. the preparation of claim 35, wherein said preparation comprises thickening agent in addition.

37. the preparation of claim 35, wherein said preparation comprises antioxidant in addition.

38. the preparation of claim 35, wherein said preparation comprises antimicrobial in addition.

39. the preparation of claim 35, wherein said preparation contains the terbinafine of salt form.

40. the preparation of claim 35, wherein said preparation contains the terbinafine of 0.5-10.0 weight %.

41. the preparation of claim 35, wherein said aqueous solution has from 4.0 to 7.5 pH.

42. the preparation of claim 35, wherein said lipid is phospholipid.

43. the preparation of claim 42, wherein the ratio of phospholipid and surfactant is 1/1-5/1w/w.

44. the preparation of claim 42, wherein said preparation contains the phospholipid of 2.0-10.0 weight %.

45. the preparation of claim 35, wherein said phospholipid is phosphatidylcholine.

46. the preparation of claim 35, wherein said preparation contains the surfactant of 1.0-5.0 weight %.

47. the preparation of claim 35, wherein said surfactant are to be selected from following nonionic surfactant: polyoxyethylene sorbitan, poly-hydroxyl ethylene stearate or poly-hydroxyl ethylene lauryl ether.

48. the preparation of claim 47, wherein said surfactant are polyoxyethylene sorbitan monoleate (Tween 80s).

49. preparation, its comprise terbinafine (10mg/g), sphingomyelins (brain) (47.944mg/g), Tween 80 (42.056mg/g), lactate (pH 4) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

50. preparation, its comprise terbinafine (15mg/g), sphingomyelins (brain) (53.750mg/g), Tween 80 (31.250mg/g), lactate (pH 4) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (15.000mg/g).

51. preparation, its comprise terbinafine (30mg/g), sphingomyelins (brain) (90.561mg/g), Tween 80 (79.439mg/g), lactate (pH 4) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

52. preparation, its comprise terbinafine (10mg/g), sphingomyelins (brain) (47.944mg/g), Tween 80 (42.056mg/g), lactate (pH 5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

53. preparation, it comprises terbinafine (5mg/g), sphingomyelins lauroyl (50.607mg/g), Brij 98 (44.393mg/g), acetate (pH 5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), EDTA (3.000mg/g) and ethanol (10.000mg/g).

54. preparation, it comprises terbinafine (30mg/g), sphingomyelins lauroyl (90.561mg/g), Brij 98 (79.439mg/g), acetate (pH 5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

55. preparation, it comprises terbinafine (7.5mg/g), sphingomyelins lauroyl (49.276mg/g), Brij 98 (79.439mg/g), acetate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

56. preparation, it comprises terbinafine (15mg/g), phosphatldylcholine and phosphatidyl glycerol (53.750mg/g), Brij 98 (31.250mg/g), phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), HTHQ (0.200mg/g), glycerol (30.000mg/g) and EDTA (3.000mg/g).

57. preparation, it comprises terbinafine (30mg/g), phosphatldylcholine and phosphatidyl glycerol (90.561mg/g), Brij 98 (79.439mg/g), phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), HTHQ (0.0200mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

58. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine and phosphatidyl glycerol (41.351mg/g), Brij 98 (48.649mg/g), phosphate (pH 4) buffer, benzyl alcohol (5.250mg/g), HTHQ (0.200mg/g), pectate thickener, glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

59. preparation, it comprises terbinafine (15mg/g), phosphatldylcholine and phosphatidyl glycerol (47.882mg/g), Brij 98 (37.118mg/g), phosphate (pH 4) buffer, benzyl alcohol (5.250mg/g), HTHQ (0.200mg/g), glycerol, EDTA (3.000mg/g) and ethanol (30.000mg/g).

60. preparation, it comprises terbinafine (30mg/g), phosphatldylcholine and phosphatidyl glycerol (95.764mg/g), Brij 98 (74.236mg/g), phosphate (pH 4) buffer, benzyl alcohol (5.250mg/g), HTHQ (0.200mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

61. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine and phosphatidylinositols (66.676mg/g), span 20 (24.324mg/g), acetate (pH 5) buffer, benzyl alcohol (5.250mg/g), HTHQ (0.200mg/g), EDTA (3.000mg/g) and ethanol (25.000mg/g).

62. preparation, it comprises terbinafine (15mg/g), phosphatldylcholine and phosphatidylinositols (62.027mg/g), span 20 (22.973mg/g), acetate (pH 5) buffer, benzyl alcohol (5.250mg/g), HTHQ (0.200mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

63. preparation, it comprises terbinafine (30mg/g), phosphatldylcholine and phosphatidylinositols (124.054mg/g), span 20 (45.946mg/g), acetate (pH 5) buffer, benzyl alcohol (5.250mg/g), HTHQ (0.200mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

64. preparation, it comprises terbinafine (5mg/g), phosphatldylcholine and phosphatidylinositols (62.687mg/g), span 20 (32.313mg/g), acetate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), HTHQ (0.200mg/g), glycerol (30.000mg/g) and EDTA (3.000mg/g).

65. preparation, it comprises terbinafine (15mg/g), phosphatldylcholine and phosphatidic acid (41.853mg/g), Tween 80 (43.147mg/g), phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

66. preparation, it comprises terbinafine (30mg/g), phosphatldylcholine and phosphatidic acid 95.764mg/g), Tween 80 (74.236mg/g), phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

67. preparation, it comprises terbinafine (15mg/g), phosphatldylcholine and phosphatidic acid (47.882mg/g), Tween 80 (37.118mg/g), phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and EDTA (3.000mg/g).

68. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine and phosphatidic acid (45.000mg/g), Tween 80 (45.000mg/g), phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and EDTA (3.000mg/g).

69. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (31.935mg/g), floating (58.065mg/g), lactate (pH 5) buffer of breast, thimerosal (5.250mg/g), BHA (0.200mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (15.000mg/g).

70. preparation, it comprises terbinafine (15mg/g), phosphatldylcholine (42.500mg/g), floating (42.500mg/g), lactate (pH 6.5) buffer of breast, thimerosal (5.250mg/g), BHA (0.200mg/g), glycerol (30.000mg/g) and EDTA (3.000mg/g).

71. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (38.276mg/g), floating (51.724mg/g), lactate (pH 4) buffer of breast, thimerosal (5.250mg/g), BHA (0.200mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

72. preparation, it comprises terbinafine (15mg/g), phosphatldylcholine (42.500mg/g), floating (42.500mg/g), lactate (pH 4) buffer of breast, thimerosal (5.250mg/g), BHA (0.200mg/g), EDTA (3.000mg/g) and ethanol (15.000mg/g).

73. preparation, it comprises terbinafine (30mg/g), phosphatldylcholine (85.000mg/g), floating (85.000mg/g), lactate (pH 4) buffer of breast, thimerosal (5.250mg/g), BHA (0.200mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

74. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (38.276mg/g), floating (51.276mg/g), lactate (pH 5) buffer of breast, thimerosal (5.250mg/g), BHA (0.200mg/g) and EDTA (3.000mg/g).

75. preparation, it comprises terbinafine (15mg/g), phosphatldylcholine (36.429mg/g), floating (48.571mg/g), lactate (pH 5) buffer of breast, thimerosal (5.250mg/g), BHA (0.200mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

76. preparation, it comprises terbinafine (30mg/g), phosphatldylcholine (72.299mg/g), floating (97.701mg/g), lactate (pH 5) buffer of breast, thimerosal (5.250mg/g), BHA (0.200mg/g), EDTA (3.000mg/g) and ethanol (15.000mg/g).

77. preparation, it comprises terbinafine (7.5mg/g), PHOSPHATIDYL ETHANOLAMINE (46.250mg/g), Tween 80 (46.250mg/g), phosphate (pH 6.5) buffer, thimerosal (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), EDTA (3.000mg/g) and ethanol (20.000mg/g).

78. preparation, it comprises terbinafine (15mg/g), PHOSPHATIDYL ETHANOLAMINE (38.804mg/g), Tween 80 (46.196mg/g), phosphate (pH 6.5) buffer, thimerosal (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (15.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

79. preparation, it comprises terbinafine (30mg/g), PHOSPHATIDYL ETHANOLAMINE (36.667mg/g), Tween 80 (33.333mg/g), phosphate (pH 6.5) buffer, thimerosal (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

80. preparation, it comprises terbinafine (10mg/g), phosphatidyl glycerol (23.333mg/g), Brij 98 (66.667mg/g), acetate (pH 4) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and EDTA (3.000mg/g).

81. preparation, it comprises terbinafine (12.5mg/g), phosphatidyl glycerol (45.833mg/g), Brij 98 (41.667mg/g), acetate (pH 4) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g), glycerol (30.000mg/g) and EDTA (3.000mg/g).

82. preparation, it comprises terbinafine (30mg/g), phosphatidyl glycerol (31.957mg/g), Brij 98 (38.043mg/g), acetate (pH 4) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

83. preparation, it comprises terbinafine (10mg/g), phosphatidyl glycerol (47.143mg/g), Brij 98 (42.857mg/g), acetate (pH 5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (25.000mg/g).

84. preparation, it comprises terbinafine (15mg/g), phosphatidyl glycerol (96.905mg/g), Brij 98 (88.095mg/g), acetate (pH 5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (20.000mg/g).

85. preparation, it comprises terbinafine (30mg/g), phosphatidyl glycerol (31.957mg/g), Brij 98 (38.043), acetate (pH 5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

86. preparation, it comprises terbinafine (10mg/g), PHOSPHATIDYL ETHANOLAMINE (35.455mg/g), floating (54.545mg/g), phosphate (pH 6.5) buffer of breast, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g) and EDTA (3.000mg/g).

87. preparation, it comprises terbinafine (15mg/g), PHOSPHATIDYL ETHANOLAMINE (84.457mg/g), floating (100.543mg/g), phosphate (pH 6.5) buffer of breast, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

88. preparation, it comprises terbinafine (30mg/g), PHOSPHATIDYL ETHANOLAMINE (89.048mg/g), floating (80.952mg/g), phosphate (pH 6.5) buffer of breast, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

89. preparation, it comprises terbinafine (10mg/g), phosphatidyl glycerol (41.087mg/g), Tween 80 (48.913mg/g), propionate (pH 4) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

90. preparation, it comprises terbinafine (15mg/g), phosphatidyl glycerol (45.280mg/g), Tween 80 (39.720mg/g), propionate (pH 4) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g) and EDTA (3.000mg/g).

91. preparation, it comprises terbinafine (30mg/g), phosphatidyl glycerol (107.500mg/g), Tween 80 (62.500mg/g), propionate (pH 4) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

92. preparation, it comprises terbinafine (5mg/g), phosphatidyl glycerol (77.243mg/g), Tween 80 (67.757mg/g), propionate (pH 4) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

93. preparation, it comprises terbinafine (15mg/g), phosphatidyl glycerol (45.280mg/g), Tween 80 (39.720mg/g), propionate (pH 5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

94. preparation, it comprises terbinafine (30mg/g), phosphatidyl glycerol (90.561mg/g), Tween 80 (79.439mg/g), propionate (pH 5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

95. preparation, it comprises terbinafine (10mg/g), phosphatidyl glycerol (47.944mg/g), Tween 80 (42.056mg/g), propionate (pH 5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), EDTA (3.000mg/g) and ethanol (10.000mg/g).

96. preparation, it comprises terbinafine (5mg/g), Phosphatidylserine (50.607mg/g) as lipid, Brij 98 (44.393mg/g), phosphate (pH 5.5) buffer, thimerosal (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g) and EDTA (3.000mg/g).

97. preparation, its comprise terbinafine (30mg/g), Phosphatidylserine (107.500mg/g) as lipid, Brij 98 (62.500mg/g) as surfactant, phosphate (pH 5.5) buffer, thimerosal (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g) and EDTA (3.000mg/g).

98. preparation, it comprises terbinafine (10mg/g), Phosphatidylserine (47.944mg/g) as lipid, Brij 98 (42.056mg/g), phosphate (pH 5.5) buffer, thimerosal (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

99. preparation, it comprises terbinafine (15mg/g), phosphatidyl glycerol (46.364mg/g), Brij 98 (38.636mg/g), acetate (pH 4) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (25.000mg/g).

100. preparation, it comprises terbinafine (15mg/g), phosphatidyl glycerol (46.364mg/g), Brij 98 (38.636mg/g), acetate (pH 4) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g), EDTA (3.000mg/g) and ethanol (20.000mg/g).

101. preparation, it comprises terbinafine (10mg/g), phosphatidyl glycerol (46.098mg/g), Brij 98 (43.902mg/g), acetate (pH 5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g), glycerol (15.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

102. preparation, it comprises terbinafine (15mg/g), phosphatidyl glycerol (43.537mg/g), Brij 98 (41.463mg/g), acetate (pH 5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g), glycerol (30.000mg/g) and EDTA (3.000mg/g).

103. preparation, it comprises terbinafine (10mg/g), phosphatidyl glycerol (45.000mg/g), Brij 98 (45.000mg/g), acetate (pH 5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

104. preparation, it comprises terbinafine (10mg/g), phosphatidyl glycerol (59.492mg/g), Brij 98 (30.508mg/g), acetate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

105. preparation, it comprises terbinafine (15mg/g), phosphatidyl glycerol (39.054mg/g), Brij 98 (45.946mg/g), acetate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and EDTA (3.000mg/g).

106. preparation, it comprises terbinafine (30mg/g), phosphatidyl glycerol (35.854mg/g), Brij 98 (34.146mg/g), acetate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g), glycerol (30.000mg/g) and EDTA (3.000mg/g).

107. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (50.000mg/g), Tween 80 (40.000mg/g), phosphate (pH 6.5), benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

108. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (38.571mg/g), Tween 80 (51.429mg/g), phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

109. preparation, it comprises terbinafine (7.5mg/g), phosphatldylcholine (41.954mg/g), Tween 80 (50.546mg/g), phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

110. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (42.632mg/g), Tween 80 (47.368mg/g), phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

111. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (46.098mg/g), Tween 80 (43.902mg/g), phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

112. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (39.721mg/g), Tween 80 (50.279mg/g), phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

113. preparation, it comprises terbinafine (5mg/g), phosphatldylcholine (44.198mg/g), Tween 80 (50.802mg/g), phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

114. preparation, it comprises terbinafine (2.5mg/g), phosphatldylcholine (46.453mg/g), Tween 80 (51.047mg/g), phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

115. preparation, it comprises terbinafine (5mg/g), phosphatldylcholine (51.221mg/g) as phospholipid, Tween 80 (43.779mg/g), phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

116. preparation, its comprise terbinafine (2.5mg/g), phosphatldylcholine (54.167mg/g) as phospholipid, Tween 80 (43.333mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

117. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (66.440mg/g), Brij 98 (23.560mg/g), phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g), and is formulated as Emulsion.

118. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (66.440mg/g), Brij 98 (23.560mg/g), phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g), and is formulated as suspensoid.

119. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (66.440mg/g), Brij 98 (23.560mg/g), phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

120. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (40.000mg/g), Tween 80 (50.000mg/g), phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g), and is formulated as Emulsion.

121. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (40.000mg/g), Tween 80 (50.000mg/g), phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g), and is formulated as suspensoid.

122. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (40.000mg/g), Tween 80 (50.000mg/g), acetate (pH 5.5) buffer, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

123. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (40.000mg/g), Tween 80 (50.000mg/g), phosphate (pH 6.5) buffer, p-Hydroxybenzoate (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

124. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (40.000mg/g), Brij 98 (50.000mg/g), phosphate (pH 6.5) buffer, benzalkonium chloride (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

125. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (40.000mg/g), Tween 80 (50.000mg/g), phosphate (pH 6.5) buffer, p-Hydroxybenzoate (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

126. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (66.440mg/g), Brij 98 (23.560mg/g), phosphate (pH 6.5) buffer, benzalkonium chloride (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

127. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (66.440mg/g), Brij 98 (23.560mg/g), phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

128. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (40.000mg/g), Tween 80 (50.000mg/g), acetate (pH 5.5) buffer, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

129. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (40.000mg/g), Tween 80 (50.000mg/g), acetate (pH 5.5) buffer, benzyl alcohol (5.250mg/g) as antimicrobial, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

130. preparation, it comprises phosphatldylcholine (44.444mg/g) as phospholipid, Tween 80 (55.556mg/g), acetate (pH 5.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

131. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (66.440mg/g), Tween 80 (23.560mg/g), acetate (pH 5.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

132. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (54.000mg/g), Tween 80 (36.000mg/g), acetate (pH 4) buffer, benzyl alcohol (5.250mg/g), BHA (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

133. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (50.000mg/g), Tween 80 (40.000mg/g), acetate (pH 4) buffer, benzyl alcohol (5.250mg/g), BHA (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

134. preparation, it comprises terbinafine (12.5mg/g), phosphatldylcholine (48.611mg/g), Tween 80 (38.889mg/g), acetate (pH 4) buffer, benzyl alcohol (5.250mg/g), BHA (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

135. preparation, it comprises terbinafine (15mg/g), phosphatldylcholine (46.575mg/g), Tween 80 (38.425mg/g), acetate (pH 4) buffer, benzyl alcohol (5.250mg/g), BHA (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g), and is formulated as Emulsion.

136. preparation, it comprises terbinafine (15mg/g), phosphatldylcholine (46.575mg/g), Tween 80 (38.425mg/g), acetate (pH 4) buffer, benzyl alcohol (5.250mg/g), BHA (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g), and is formulated as suspensoid.

137. preparation, it comprises terbinafine (15mg/g), phosphatldylcholine (46.575mg/g), Tween 80 (38.425mg/g), acetate (pH 4) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

138. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (50.000mg/g), Tween 80 (40.000mg/g), acetate (pH 4.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

139. preparation, it comprises terbinafine (30mg/g), phosphatldylcholine (94.444mg/g), Tween 80 (75.556mg/g), acetate (pH 4) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

140. preparation, it comprises terbinafine (15mg/g), phosphatldylcholine (46.712mg/g), Tween 80 (38.288mg/g), acetate (pH 4), benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

141. preparation, it comprises terbinafine (12mg/g), phosphatldylcholine (48.889mg/g), Tween 80 (39.111mg/g), acetate (pH 4), benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

142. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (39.721mg/g), Tween 80 (50.279mg/g), phosphate (pH 6.5) buffer, benzyl alcohol (5.25mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

143. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (90.000mg/g), phosphate buffer (pH 6.5), benzyl alcohol, BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

144. preparation, it comprises terbinafine (15mg/g), phosphatldylcholine (46.575mg/g), Tween 80 (38.425mg/g), phosphate (pH 4) buffer, BHT (0.500mg/g) and sodium pyrosulfite (0.200) and EDTA (3.000mg/g), and is formulated as Emulsion.

145. preparation, it comprises terbinafine (15mg/g), phosphatldylcholine (46.575mg/g), Tween 80 (38.425mg/g), phosphate (pH 4) buffer, BHT (0.500mg/g) and sodium pyrosulfite (0.200) and EDTA (3.000mg/g), and is formulated as suspensoid.

146. preparation, it comprises terbinafine (15mg/g), phosphatldylcholine (54.643mg/g), Tween 80 (30.357mg/g), phosphate (pH 4) buffer, BHA (0.500mg/g) and sodium pyrosulfite (0.200) and EDTA (3.000mg/g).

147. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (39.72mg/g), Tween 80 (50.279mg/g), phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) and ethanol (30.000mg/g).

148. preparation, it comprises terbinafine (10mg/g), phosphatldylcholine (90.00mg/g), phosphate (pH 6.5) buffer, benzyl alcohol (5.250mg/g), BHT (0.200mg/g) and sodium pyrosulfite (0.500mg/g), glycerol (30.000mg/g), EDTA (3.000mg/g) as chelating agen and ethanol (30.000mg/g).

149. preparation, it comprises terbinafine (15mg/g), phosphatldylcholine (46.57mg/g), Tween 80 (38.425mg/g), phosphate (pH 4) buffer, BHT (0.500mg/g) and sodium pyrosulfite (0.200mg/g) and EDTA (3.000mg/g), and is formulated as Emulsion.

150. preparation, it comprises terbinafine (15mg/g), phosphatldylcholine (46.57mg/g), Tween 80 (38.425mg/g), phosphate (pH 4) buffer, BHT (0.500mg/g) and sodium pyrosulfite (0.200mg/g) and EDTA (3.000mg/g), and is formulated as suspensoid.

151. preparation, it comprises terbinafine (15mg/g), phosphatldylcholine (54.64mg/g), Tween 80 (30.357mg/g), phosphate (pH 4) buffer, BHA (0.500mg/g) and sodium pyrosulfite (0.200) as antioxidant and EDTA (3.000mg/g).

152. test kit, the description that it is included among the claim 49-151 in the container each preparation and uses said preparation treatment fungal infection.

153. comprise the pharmaceutical preparation of terbinafine, lipid and surfactant, wherein said preparation is mixed with the fungal infection that is used for the treatment of fingernail and skin.

154. terbinafine is applied to the method for human nail tissue, described method comprises fingernail and/or the surrounding skin that preparation is applied to partly the human experimenter, wherein said preparation comprises terbinafine, lipid and surfactant, and wherein said using produces the terbinafine mean concentration of every gram nail tissue at least about 2.5mg/g; Wherein at least 2 weeks after stopping to use described preparation, measure mean concentration; And the wherein said terbinafine average serum concentration that produces among the human experimenter less than 10ng/mL that is applied in.

155. terbinafine is applied to the method for human nail tissue, described method comprises fingernail and/or the surrounding skin that preparation is applied to partly the human experimenter, wherein said preparation comprises terbinafine, lipid and surfactant, and wherein said using produces every gram nail tissue at least about at least about 0.1 to about 15.0mg/g terbinafine mean concentration; Wherein at least 2 weeks after stopping to use described preparation, measure mean concentration; And the wherein said terbinafine average serum concentration that produces among the human experimenter less than 10ng/mL that is applied in.

156. the method for claim 154 and 155, the wherein said terbinafine average serum concentration that produces among the human experimenter less than 5ng/mL that is applied in.

157. the method for claim 154 and 155, the wherein said terbinafine average serum concentration that produces among the human experimenter less than 1ng/mL that is applied in.

158. the method for claim 154 and 155, wherein said preparation comprise about 3.0mg terbinafine.

159. the method for claim 158, wherein said preparation administration every day 2 times.

160. the method for claim 159, wherein said at least 2 weeks of preparation administration.

161. the method for claim 154 and 155, the lipid in the wherein said preparation is phospholipid.

162. the method for claim 154 and 155, the terbinafine in the wherein said preparation is a salt form.

163. the method that treatment human experimenter's nail fungi infects, described method comprises that the preparation that will comprise terbinafine, lipid and surfactant is locally applied to infected fingernail and/or surrounding skin, every day 2 times, continues at least 3 weeks.

164. the method for claim 163, wherein said preparation comprise about 1.0 to about 5.0mg terbinafine.

165. the method for claim 164, wherein said preparation comprise about 3.0mg terbinafine.

166. the method for claim 165, the lipid in the wherein said preparation is phospholipid.

167. the method for claim 166, the terbinafine in the wherein said preparation is a salt form.

168. the method that treatment human experimenter's nail fungi infects, described method comprises preparation is applied to infected fingernail and/or surrounding skin partly, the wherein said terbinafine mean concentration that produces the about 2.5mg/g of every gram nail tissue of using, wherein 2 weeks after stopping to use described preparation, measure mean concentration; And the wherein said terbinafine average serum concentration that produces among the human experimenter less than 10ng/mL that is applied in; And wherein said preparation comprises terbinafine, lipid and surfactant.

169. the method for claim 154 and 155, the wherein said terbinafine average serum concentration that produces among the human experimenter less than 5ng/mL that is applied in.

170. the method for claim 154 and 155, the wherein said terbinafine average serum concentration that produces among the human experimenter less than 1ng/mL that is applied in.

171. claim 168,169 or 170 method, wherein said pharmaceutical composition comprises about 3.0mg terbinafine.

172. the method for claim 171, wherein said pharmaceutical composition administration every day 2 times.

173. the method for claim 172, wherein said at least 3 weeks of pharmaceutical composition administration.

174. the method for claim 173, the lipid in the wherein said pharmaceutical composition is phospholipid.

175. the method for claim 174, the terbinafine in the wherein said pharmaceutical composition is a salt form.

176. the method for fungal infection of treatment human experimenter's nail tissue, it comprises the infected fingernail that preparation is applied to the human experimenter, every day 2 times, continues at least 3 weeks, and wherein said preparation comprises terbinafine, lipid and surfactant; After using at least 3 weeks, assessment experimenter's mycology is cured, need to determine whether additional procedures.

177. the method for claim 176, wherein said preparation comprise about 1.0 to about 5.0mg terbinafine.

178. the method for claim 177, wherein said preparation comprise about 3.0mg terbinafine.

179. the method for claim 178, the lipid in the wherein said preparation is phospholipid.

180. the method for claim 179, the terbinafine in the wherein said preparation is a salt form.

181. the method for treatment human experimenter's fungal infection, described method comprises the pharmaceutical preparation that comprises formula I chemical compound, lipid and surfactant to experimenter's local application; Its Chinese style I chemical compound has following structural formula

Wherein

(a) R ¹The group of expression following formula

R ⁹Expression hydrogen, halogen, hydroxyl, low alkyl group or lower alkoxy,

P is 1,2 or 3,

R is 1,2 or 3,

S is 3,4 or 5,

T is 2,3 or 4, and

V is 3,4,5 or 6;

R ³And R ⁵Represent hydrogen or low alkyl group independently, and

R ⁴Expression C _1-6Alkyl or C _3-8Cycloalkyl-(C _1-6)-alkyl; And

R ⁶The group of expression following formula

R wherein ¹¹Expression hydrogen, (C _1-6) alkyl, the alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, phenyl, benzene alkyl or the thienyl that replace of Alpha-hydroxy randomly,

Expression C _5-8Cycloalkylidene, its optional pair keys that contain; Or

(b) R ¹Represent as group at (a) undefined formula IIa to IIg,

R ²Expression hydrogen or low alkyl group,

R ⁵And R ⁶Has the implication that under (a), provides.

182. the formula I chemical compound that will effectively treat the amount of tinea unguium is delivered to the method for fingernail, described method comprises the pharmaceutical preparation that comprises formula I chemical compound, lipid and the surfactant for the treatment of effective dose to experimenter's local application; Its Chinese style I chemical compound has following structural formula

Wherein

(a) R ¹The group of expression following formula

R ⁹Expression hydrogen, halogen, hydroxyl, low alkyl group or lower alkoxy,

P is 1,2 or 3,

R is 1,2 or 3,

S is 3,4 or 5,

T is 2,3 or 4, and

V is 3,4,5 or 6;

R ³And R ⁵Represent hydrogen or low alkyl group independently, and

R ⁴Expression C _1-6Alkyl or C _3-8Cycloalkyl-(C _1-6)-alkyl; And

R ⁶The group of expression following formula

Expression C _5-8Cycloalkylidene, its optional pair keys that contain; Or

(b) R ¹Represent as group at (a) undefined formula IIa to IIg,

R ²Expression hydrogen or low alkyl group,

R ⁵And R ⁶Has the implication that under (a), provides.

183. preparation, it is included in formula I chemical compound, lipid and surfactant in the aqueous solution, and wherein said preparation is fit to local delivery; Its Chinese style I chemical compound has following structural formula

Wherein

(a) R ¹The group of expression following formula

Therefore in formula IIa to IIi, so in formula IIa to IIi, R ⁷And R ⁸Represent independently hydrogen, halogen, trifluoromethyl, hydroxyl, nitro, low alkyl group, lower alkoxy or-C (=O)-R ¹⁵, R wherein ¹⁵Expression H, hydroxyl, low alkyl group, alkoxyl (make R ¹⁵With carbonyl is ester) or amino (make R ¹⁵With carbonyl is carbamoyl);

R ⁹Expression hydrogen, halogen, hydroxyl, low alkyl group or lower alkoxy,

P is 1,2 or 3,

R is 1,2 or 3,

S is 3,4 or 5,

T is 2,3 or 4, and

V is 3,4,5 or 6;

R ³And R ⁵Represent hydrogen or low alkyl group independently, and

R ⁴Expression C _1-6Alkyl or C _3-8Cycloalkyl-(C _1-6)-alkyl; And

R ⁶The group of expression following formula

Expression C _5-8Cycloalkylidene, its optional pair keys that contain; Or

(b) R ¹Represent as group at (a) undefined formula IIa to IIg,

R ²Expression hydrogen or low alkyl group,

R ⁵And R ⁶Has the implication that under (a), provides.

184. comprise the pharmaceutical preparation of formula I chemical compound, lipid and surfactant, wherein said preparation is mixed with the fungal infection that is used for the treatment of fingernail and skin; Its Chinese style I chemical compound has following structural formula

Wherein

(a) R ¹The group of expression following formula

R ⁹Expression hydrogen, halogen, hydroxyl, low alkyl group or lower alkoxy,

P is 1,2 or 3,

R is 1,2 or 3,

S is 3,4 or 5,

T is 2,3 or 4, and

V is 3,4,5 or 6;

R ³And R ⁵Represent hydrogen or low alkyl group independently, and

R ⁴Expression C _1-6Alkyl or C _3-8Cycloalkyl-(C _1-6)-alkyl; And

R ⁶The group of expression following formula

Expression C _5-8Cycloalkylidene, its optional pair keys that contain; Or

(b) R ¹Represent as group at (a) undefined formula IIa to IIg,

R ²Expression hydrogen or low alkyl group,

R ⁵And R ⁶Has the implication that under (a), provides.

185. formula I compound administration is given the method for human nail tissue, described method comprises fingernail and/or the surrounding skin that preparation is applied to partly the human experimenter, wherein said preparation comprises formula I chemical compound, lipid and surfactant, and wherein said using produces the formula I chemical compound mean concentration of every gram nail tissue at least about 2.5mg/g; Wherein at least 2 weeks after stopping to use described preparation, measure mean concentration; And the wherein said formula I chemical compound average serum concentration that produces among the human experimenter less than 10ng/mL that is applied in; Its Chinese style I chemical compound has following structural formula

Wherein

(a) R ¹The group of expression following formula

R ⁹Expression hydrogen, halogen, hydroxyl, low alkyl group or lower alkoxy,

P is 1,2 or 3,

R is 1,2 or 3,

S is 3,4 or 5,

T is 2,3 or 4, and

V is 3,4,5 or 6;

R ³And R ⁵Represent hydrogen or low alkyl group independently, and

R ⁴Expression C _1-6Alkyl or C _3-8Cycloalkyl-(C _1-6)-alkyl; And

R ⁶The group of expression following formula

Expression C _5-8Cycloalkylidene, its optional pair keys that contain; Or

(b) R ¹Represent as group at (a) undefined formula IIa to IIg,

R ²Expression hydrogen or low alkyl group,

R ⁵And R ⁶Has the implication that under (a), provides.

186. formula I compound administration is given the method for human nail tissue, described method comprises fingernail and/or the surrounding skin that preparation is applied to partly the human experimenter, wherein said preparation comprises formula I chemical compound, lipid and surfactant, and wherein said using produces every gram nail tissue at least about at least about 0.1 to about 15.0mg/g formula I chemical compound mean concentration; Wherein at least 2 weeks after stopping to use described preparation, measure mean concentration; And the wherein said formula I chemical compound average serum concentration that produces among the human experimenter less than 10ng/mL that is applied in; Its Chinese style I chemical compound has following structural formula

Wherein

(a) R ¹The group of expression following formula

R ⁹Expression hydrogen, halogen, hydroxyl, low alkyl group or lower alkoxy,

P is 1,2 or 3,

R is 1,2 or 3,

S is 3,4 or 5,

T is 2,3 or 4, and

V is 3,4,5 or 6;

R ³And R ⁵Represent hydrogen or low alkyl group independently, and

R ⁴Expression C _1-6Alkyl or C _3-8Cycloalkyl-(C _1-6)-alkyl; And

R ⁶The group of expression following formula

Expression C _5-8Cycloalkylidene, its optional pair keys that contain; Or

(b) R ¹Represent as group at (a) undefined formula IIa to IIg,

R ²Expression hydrogen or low alkyl group,

R ⁵And R ⁶Has the implication that under (a), provides.

187. the method that treatment human experimenter's nail fungi infects, described method comprises that the preparation that will comprise formula I chemical compound, lipid and surfactant is applied to infected fingernail and/or surrounding skin partly, every day 2 times, continues at least 3 weeks; Its Chinese style I chemical compound has following structural formula

Wherein

(a) R ¹The group of expression following formula

R ⁹Expression hydrogen, halogen, hydroxyl, low alkyl group or lower alkoxy,

P is 1,2 or 3,

R is 1,2 or 3,

S is 3,4 or 5,

T is 2,3 or 4, and

V is 3,4,5 or 6;

R ³And R ⁵Represent hydrogen or low alkyl group independently, and

R ⁴Expression C _1-6Alkyl or C _3-8Cycloalkyl-(C _1-6)-alkyl; And

R ⁶The group of expression following formula

Expression C _5-8Cycloalkylidene, its optional pair keys that contain; Or

(b) R ¹Represent as group at (a) undefined formula IIa to IIg,

R ²Expression hydrogen or low alkyl group,

R ⁵And R ⁶Has the implication that under (a), provides.

188. the method that treatment human experimenter's nail fungi infects, described method comprises preparation is applied to infected fingernail and/or surrounding skin partly, the wherein said formula I chemical compound mean concentration that produces the about 2.5mg/g of every gram nail tissue of using, wherein 2 weeks after stopping to use described preparation, measure mean concentration; And the wherein said formula I chemical compound average serum concentration that produces among the human experimenter less than 10ng/mL that is applied in; And

Wherein said preparation comprises formula I chemical compound, lipid and surfactant; And

Its Chinese style I chemical compound has following structural formula

Wherein

(a) R ¹The group of expression following formula

R ⁹Expression hydrogen, halogen, hydroxyl, low alkyl group or lower alkoxy,

P is 1,2 or 3,

R is 1,2 or 3,

S is 3,4 or 5,

T is 2,3 or 4, and

V is 3,4,5 or 6;

R ³And R ⁵Represent hydrogen or low alkyl group independently, and

R ⁴Expression C _1-6Alkyl or C _3-8Cycloalkyl-(C _1-6)-alkyl; And

R ⁶The group of expression following formula

Expression C _5-8Cycloalkylidene, its optional pair keys that contain; Or

(b) R ¹Represent as group at (a) undefined formula IIa to IIg,

R ²Expression hydrogen or low alkyl group,

R ⁵And R ⁶Has the implication that under (a), provides.

189. the method for fungal infection of treatment human experimenter's nail tissue, it comprises the infected fingernail that preparation is applied to the human experimenter, every day 2 times, continues at least 3 weeks, and wherein said preparation comprises formula I chemical compound, lipid and surfactant; Its Chinese style I chemical compound has following structural formula

Wherein

(a) R ¹The group of expression following formula

R ⁹Expression hydrogen, halogen, hydroxyl, low alkyl group or lower alkoxy,

P is 1,2 or 3,

R is 1,2 or 3,

S is 3,4 or 5,

T is 2,3 or 4, and

V is 3,4,5 or 6;

R ³And R ⁵Represent hydrogen or low alkyl group independently, and

R ⁴Expression C _1-6Alkyl or C _3-8Cycloalkyl-(C _1-6)-alkyl; And

R ⁶The group of expression following formula

Expression C _5-8Cycloalkylidene, its optional pair keys that contain; Or

(b) R ¹Represent as group at (a) undefined formula IIa to IIg,

R ²Expression hydrogen or low alkyl group,

R ⁵And R ⁶Has the implication that under (a), provides.